Benzoheterocyclic compounds

ABSTRACT

Novel 4-oxoquinoline-3-carboxylic acid compounds of the formula: ##STR1## wherein R 1  is cyclopropyl which may have 1 to 3 substituents of alkyl and halogen; phenyl which may be substituted by 1 to 3 substituents of alkoxy, halogen and OH; alkyl which may be substituted by halogen, alkanoyloxy or OH; alkenyl; or thienyl, R 2  is 5- to 9-membered saturated or unsaturated heterocyclic ring which may be substituted, R 3  is alkyl, R is H or alkyl, and X is halogen, and pharmaceutically acceptable salts thereof, said compounds having excellent antimicrobial activity and hence being useful as an antimicrobial agent, and a pharmaceutical composition containing said compound as an active ingredient.

This application is a continuation of U.S. application Ser. No.07/535,344 filed Jun. 8, 1990 (abandoned) which is a divisional of Ser.No. 07/179,239 filed Apr. 8, 1988.

The present invention relates to novel antimicrobial benzoheterocycliccompounds of the formula [1]: ##STR2## wherein R¹ is a cyclopropyl whichmay be substituted by 1 to 3 of substituents selected from the groupconsisting of a (lower) alkyl and a halogen atom, a phenyl which may besubstituted by 1 to 3 of substituents selected from the group consistingof a (lower) alkoxy, a halogen atom and hydroxy on phenyl ring, a(lower) alkyl which may be substituted by a halogen atom, a (lower)alkanoyloxy or hydroxy, a (lower) alkenyl or thienyl, R² is a 5- to9-membered saturated or unsaturated heterocyclic ring which may besubstituted, R³ is a (lower) alkyl, R is hydrogen atom or a (lower)alkyl, and X is a halogen atom, and pharmaceutically acceptable saltsthereof

The benzoheterocyclic compounds of the formula [1] and salts thereofhave excellent antibacterial activities against various gram positiveand gram negative bacteria, and are useful for the treatment of variousinfectious diseases induced by various bacteria in human, other animalsand fish and are also useful as an external antimicrobial ordisinfectant agent for medical instruments or the like.

Prior art

There are many publications which disclose 4-oxoquinoline-3-carboxylicacid derivatives useful as antibacterial agents. Among thesepublications, European Patent Publication No. 178388 discloses1-cyclopropyl-7-piperazinodihydroquinoline carboxylic acid derivativesof the formula: ##STR3## wherein R¹ is H or lower alkyl, R² is H,methyl, p-nitro(or amino)-benzyl, R³ is H, methyl, or aminomethyl, and Yis Cl or F.

Japanese Patent First Publication (Kokai) No. 469/1987 discloses1-cyclopropyl-dihydroquinoline carboxylic acid derivatives of theformula: ##STR4## wherein R is substituted or unsubstituted pyrrolidinylor piperazinyl.

WO 8606630 discloses1-cycloalkyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid derivatives ofthe formula: ##STR5## wherein R¹ is C₃ -C₆ cycloalkyl, Y is optionallysubstituted 6-membered aromatic group.

U.S. Pat. No. 4,556,658 discloses 7-amino-1-cyclopropyl-3-quinolinecarboxylic acid derivatives of the formula: ##STR6## wherein R¹ and R²are each substituted or unsubstituted alkyl, or both may combinetogether with N atom to form a 5- or 6-membered heterocyclic ring.

Belgian Patent 899399 discloses1-cyclopropyl-7-piperazinyl-dihydroquinoline carboxylic acid derivativesof the formula: ##STR7## wherein R is H, methyl, or p-nitro(oramino)-benzyl, R¹ is H or lower alkyl, and Y is Cl, F, methyl.

Similar 1-substituted-7-heterocyclic group-substituted dihydroquinolinecarboxylic acid derivatives are also disclosed in other publications.

However, these known publications do not disclose any compound having analkyl substituent at the 5-position.

BRIEF DESCRIPTION OF THE INVENTION

The object of the present invention is to provide novelbenzoheterocyclic compounds of the formula [1] and salts thereof whichhave excellent antimicrobial activity and excellent absorbability.Another object of the invention is to provide a pharmaceuticalcomposition containing as an active ingredient a compound of the formula[1] or a pharmaceutically acceptable salt thereof, which is useful forthe treatment of various infectious diseases. These and other objects ofthe invention will be apparent to persons skilled in the art from thefollowing description.

DETAILED DESCRIPTION OF THE INVENTION

The novel benzoheterocyclic compounds of the present invention have theformula [1] as shown above and include pharmaceutically acceptable saltsthereof.

In the specification, the term "a halogen atom" includes fluorine,chlorine, bromine or iodine atom.

The term "a cyclopropyl which may be substituted by 1 to 3 ofsubstituents selected from the group consisting of a (lower) alkyl and ahalogen atom" includes cyclopropyl which may be substituted by 1 to 3 ofsubstituents selected from the group consisting of a straight chain orbranched chain C₁ -C₆ alkyl and a halogen atom, such as cyclopropyl,2-fluoro-1-cyclopropyl, 2-chloro-1-cyclopropyl, 2-bromo-1-cyclopropyl,2-iodo-1-cyclopropyl, 2,2-dichloro-1-cyclopropyl,2,2-dibromo-1-cyclopropyl, 2,2,3-trichloro-1-cyclopropyl,2-methyl-1-cyclopropyl, 2-ethyl-1-cyclopropyl, 2-propyl-1-cyclopropyl,2-butyl-1-cyclopropyl, 2-pentyl-1-cyclopropyl, 2-hexyl-1-cyclopropyl,2,2-dimethyl-1-cyclopropyl, 2,3-dimethyl-1-cyclopropyl,2,2,3-trimethyl-1-cyclopropyl, 2-fluoro-3-methyl-1-cyclopropyl,2,2-diethyl-1-cyclopropyl, 2-methyl-3-propyl-1-cyclopropyl, and thelike.

The term "a (lower) alkyl" includes straight chain or branched chain C₁-C₆ alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,pentyl, hexyl, etc.

The term "a 5- to 9-membered saturated or unsaturated heterocyclic ringwhich may be substituted" denotes a 5- to 9-membered saturated orunsaturated heterocyclic ring which may be substituted by a (lower)alkyl; a cycloalkyl; a phenyl (lower) alkyl in which the phenyl ring maybe substituted by a lower alkoxy, nitro or amino; a phenyl which may besubstituted by a halogen atom or a (lower) alkyl optionally substitutedby 1 to 3 of halogen atoms; a pyridyl; a (lower) alkyl having 1 to 3substituents selected from the group consisting of hydroxy, an aminowhich may be substituted by a (lower) alkyl, a (lower) alkanoyl, acycloalkyl or a (lower) alkoxycarbonyl, a (lower) alkoxy and a halogenatom; a (lower) alkynyl; a (lower) alkanoyl which may be substituted by1 to 7 of halogen atoms; a (lower) alkenylcarbonyl having 1 to 3substituents selected from the group consisting of a halogen atom and acarboxy; a (lower) alkoxycarbonyl; an aminocarbonyl which may besubstituted by a (lower) alkyl; a phenyl(lower)alkoxycarbonyl; anamino(lower)alkanoyl which may be substituted by aphenyl(lower)alkoxycarbonyl; a (lower) alkoxycarbonyl(lower)alkyl; acarboxy(lower)alkyl; an anilinocarbonyl(lower)alkyl; an amino which maybe substituted by a (lower) alkyl, a phenyl(lower)alkyl, a (lower)alkoxycarbonyl or a (lower) alkanoyl; hydroxy; a (lower) alkylsulfonylwhich may be substituted by 1 to 3 of halogen atoms; phthalide; a2(5H)-furanone which may be substituted by 1 or 2 of halogen atoms; asulfo(lower)alkyl; oxo; a (lower) alkoxy; a (lower) alkenyl; a halogenatom; a (lower) alkanoyloxy; a 2-oxo-1,3-dioxolenemethyl which may besubstituted by phenyl or a (lower) alkyl; a cycloalkylamino; a2-oxo-1,3-dioxolenemethylamino which may be substituted by phenyl or a(lower) alkyl; a (lower) alkylthio; or thio, and includes morespecifically 5- to 9-membered saturated or unsaturated heterocyclicrings which may be substituted by 1 to 3 of substituents selected fromthe group consisting of a straight chain or branched chain C₁ -C₆ alkyl;a C₃ -C₈ cycloalkyl; a phenylalkyl in which phenyl ring may besubstituted by a straight chain or branched chain C₁ -C₆ alkoxy, nitroor amino and the alkyl moiety is a straight chain or branched chain C₁-C₆ alkyl; a phenyl in which the phenyl ring may be substituted by ahalogen atom or by a straight chain or branched chain C₁ -C₆ alkyl whichmay be substituted by 1 to 3 of halogen atoms; a pyridyl; an amino whichmay be substituted by 1 or 2 substituents selected from the groupconsisting of hydroxy, a straight chain or branched chain C₁ -C₆ alkyl,a straight or branched chain C₁ -C₆ alkanoyl, a C₃ -C₈ cycloalkyl and astraight chain or branched chain (C₁ -C₆)alkoxy-carbonyl; a straightchain or branched chain C₁ -C₆ alkyl having 1 to 3 of substituentsselected from the group consisting of a straight chain or branched chainC₁ -C₆ alkoxy group and a halogen atom; a straight chain or branchedchain C₂ -C₆ alkynyl; a straight chain or branched chain C₁ -C₆ alkanoylwhich may be substituted by 1 to 7 of halogen atoms; a straight chain orbranched chain (C₂ -C₆)alkenyl-carbonyl substituted by 1 to 3 of halogenatoms or carboxy; a straight chain or branched chain (C₁-C₆)alkoxy-carbonyl; an aminocarbonyl which may be substituted by 1 or 2of a straight chain or branched chain C₁ -C₆ alkyl group; aphenylalkoxycarbonyl in which the alkoxy moiety is a straight chain orbranched chain C₁ -C₆ alkoxy; a straight chain or branched chain C₂ -C₆aminoalkanoyl which may be substituted by a phenylalkoxycarbonyl inwhich the alkoxy moiety is a straight chain or branched chain C₁ -C₆alkoxy; an alkoxycarbonylalkyl in which the alkoxy and alkyl moietiesare straight chain or branched chain C₁ -C₆ alkoxy and alkyl,respectively; a carboxyalkyl in which the alkyl moiety is a straightchain or branched chain C₁ -C₆ alkyl; an anilinocarbonylalkyl in whichthe alkyl moiety is a straight chain or branched chain C₁ -C₆ alkyl: anamino which may be substituted by 1 or 2 of a straight chain or branchedchain C₁ -C₆ alkyl, a phenylalkyl in which the alkyl moiety is astraight chain or branched chain C₁ -C₆ alkyl, a straight chain orbranched chain (C₁ -C₆)alkoxy-carbonyl, or a straight chain or branchedchain C₁ -C₆ alkanoyl: hydroxy; a straight chain or branched chain C₁-C₆ alkylsulfonyl which may be substituted by 1 to 3 of halogen atoms;phthalide; a 2(5H)-furanone which may be substituted by 1 or 2 ofhalogen atoms; a sulfoalkyl in which the alkyl moiety is a straightchain or branched chain C₁ -C₆ alkyl; oxo; a straight chain or branchedchain C₁ -C₆ alkoxy; a straight chain or branched chain C₂ -C₆ alkenyl;a halogen atom; a straight chain or branched chain C₂ -C₆ alkanoyloxy; aC₃ -C₈ cycloalkylamino; a straight chain or branched chain C₁ -C₆alkylthio; thio; a 2-oxo-1,3-dioxolenemethyl which may be substituted byphenyl or a straight chain or branched chain C₁ -C₆ alkyl; and a2-oxo-1,3-dioxolenemethylamino which may be substituted by phenyl or astraight chain or branched chain C₁ -C₆ alkyl, such as, for example,piperazinyl, piperidinyl, pyrrolidinyl, homopiperazinyl, morpholino,thiomorpholino, 1,2,5,6-tetrahydropyridyl, imidazolyl,1,4-diazabicyclo[4.3.0]nonan-4-yl, thiomorpholino-4-oxide,thiomorpholino-4,4-dioxide, pyrazolidinyl, hexahydropyridazinyl,pyridyl, thiazolidinyl, 2-thio-1-imidazolidinyl, 2-oxo-1-imidazolidinyl,3,7-diazabicyclo[4.3.0]nonan-3-yl, 4-methyl-1-piperazinyl,4-ethyl-1-piperazinyl, 4-propyl-1-piperazinyl, 4-t-butyl-1-piperazinyl,4-pentyl-1-piperazinyl, 4-hexyl-1-piperazinyl, 3-methyl-1-piperazinyl,3,4-dimethyl-1-piperazinyl, 2,5-dimethyl-1-piperazinyl,2,4,5-trimethyl-1-piperazinyl, 3,4,5-trimethyl-1-piperazinyl,3-ethyl-1-piperazinyl, 3-propyl-4-methyl-1-piperazinyl,2-n-butyl-5-methyl-1-piperazinyl, 2-pentyl-5-hexyl-1-piperazinyl,4-formyl-1-piperazinyl, 4-acetyl-1-piperazinyl,4-propionyl-1-piperazinyl, 4-butyryl-1-piperazinyl,4-pentanoyl-1-piperazinyl, 4-hexanoyl-1-piperazinyl,4-(α,α,α-trifluoroacetyl)-1-piperazinyl,4-(β,β,β-trifluoro-α,α-difluoropropionyl)-1-piperazinyl,4-(γ,γ,γ-trifluoro-β,β-difluoro-α,.alpha.-difluorobutyryl)-1-piperazinyl,4-(α,α-dichloroacetyl)-1 -piperazinyl, 4-(α-bromoacetyl)-1-piperazinyl,4-(α-iodoacetyl)-1-piperazinyl, 4-(α-fluoropropionyl)-1-piperazinyl,4-(β-fluoro-α-fluoropropionyl)-1-piperazinyl,4-(6-fluorohexanoyl)-1-piperazinyl, 4-(4-chloropentanoyl)-1-piperazinyl,4-benzyl-1-piperazinyl, 4-(2-phenylethyl)-1-piperazinyl,4-(1-phenylethyl)-1-piperazinyl, 4-(3-phenylpropyl)-1-piperazinyl,4-(4-phenylbutyl)-1-piperazinyl,4-(1,1-dimethyl-2-phenylethyl)-1-piperazinyl,4-(5-phenylpentyl)-1-piperazinyl, 4-(6-phenylhexyl)-1-piperazinyl,4-(2-methyl-3-phenylpropyl)-1-piperazinyl, 4-amino-1-piperazinyl,3-amino-1-piperazinyl, 2-amino-1-piperazinyl,4-methylamino-1-piperazinyl, 3-dimethylamino-1-piperazinyl,2-ethylamino-1-piperazinyl, 4-propylamino-1-piperazinyl,4-t-butylamino-1-piperazinyl, 3-pentylamino-1-piperazinyl,2-hexylamino-1-piperazinyl, 4-diethylamino-1-piperazinyl,4-(N-methyl-N-n-butylamino)-1-piperazinyl,3-(N-methyl-N-pentylamino)-1-piperazinyl,2-(N-ethyl-N-hexylamino)-1-piperazinyl, 4-acetylamino-1-piperazinyl,3-formylamino-1-piperazinyl, 2-propionylamino-1-piperazinyl,4-butyrylamino-1-piperazinyl, 3-pentanoylamino-1-piperazinyl,2-hexanoylamino-1-piperazinyl, 4-(N-methyl-N-acetylamino)-1-piperazinyl,3-(N-ethyl-N-propionylamino)-1-piperazinyl, 4-hydroxy-1-piperazinyl,3-hydroxy-1-piperazinyl, 2-hydroxy-1-piperazinyl,4-methylsulfonyl-1-piperazinyl, 4-ethylsulfonyl-1-piperazinyl,4-propylsulfonyl-1-piperazinyl, 4-n-butylsulfonyl-1-piperazinyl,4-pentylsulfonyl-1-piperazinyl, 4-hexylsulfonyl-1-piperazinyl,4-trifluoromethylsulfonyl-1-piperazinyl,4-(2-fluoroethylsulfonyl)-1-piperazinyl,4-(3-fluoropropylsulfonyl)-1-piperazinyl,4-(4,4,4-trifluorobutylsulfonyl)-1-piperazinyl,4-sulfonyl-1-piperazinyl, 4-(phthalid-3-yl)-1-piperazinyl,4-(3,4-dibromo-2(5H)-furanon-5-yl)-1-piperazinyl,4-(3,4-dichloro-2(5H)-furanon-5-yl)-1-piperazinyl,4-(2(5H)-furanon-5-yl)-1-piperazinyl,4-(3-chloro-2(5H)-furanon-5-yl)-1-piperazinyl,4-formyl-3-methyl-1-piperazinyl, 4-acetyl-3-ethyl-1-piperazinyl,4-acetyl-2-methyl-1-piperazinyl, 4-methyl-3-hydroxymethyl-1-piperazinyl,3-hydroxymethyl-1-piperazinyl, 4-ethyl-3-(2-hydroxyethyl)-1-piperazinyl,3-(3-hydroxypropyl)-1-piperazinyl,4-methyl-2-(4-hydroxybutyl)-1-piperazinyl,4-ethyl-3-(5-hydroxypentyl)-1-piperazinyl,3-(6-hydroxyhexyl)-1-piperazinyl, 4-(4-methoxybenzyl)-1-piperazinyl,4-(3-ethoxybenzyl)-1-piperazinyl, 4-(2-propoxybenzyl)-1-piperazinyl,4-(4-n-butoxybenzyl)-1-piperazinyl, 4-(3-pentyloxybenzyl)-1-piperazinyl,4-(2-hexyloxybenzyl)-1-piperazinyl, 4-(4-nitrobenzyl)-1-piperazinyl,4-(3-nitrobenzyl)-1-piperazinyl, 4-(4-aminobenzyl)-1-piperazinyl,4-(2-aminobenzyl)-1-piperazinyl, 4-cyclopropyl-1-piperazinyl,4-cyclobutyl-1-piperazinyl, 4-cyclopentyl-1-piperazinyl,4-cyclohexyl-1-piperazinyl, 4-cycloheptyl-1-piperazinyl,4-cyclooctyl-1-piperazinyl, 4-phenyl-1-piperazinyl,4-(4-fluorophenyl)-1-piperazinyl, 4-(3-bromophenyl)-1-piperazinyl,4-(2-chlorophenyl)-1-piperazinyl, 4-(4-iodophenyl)-1-piperazinyl,4-(4-methylphenyl)-1-piperazinyl, 4-(3-ethylphenyl)-1-piperazinyl,4-(2-propylphenyl)-1-piperazinyl, 4-(4-n-butylphenyl)-1-piperazinyl,4-(3-pentylphenyl)-1-piperazinyl, 4-(2-hexylphenyl)-1-piperazinyl,4-(4-trifluoromethylphenyl)-1-piperazinyl,4-[3-(2-chloroethyl)phenyl]-1-piperazinyl,4-[2-(3,3-dibromopropyl)phenyl]-1-piperazinyl,4-[4-(4-chlorobutyl)phenyl]-1-piperazinyl,4-hydroxymethyl-1-piperazinyl, 4-(2-hydroxyethyl)-1-piperazinyl,4-(3-hydroxypropyl)-1-piperazinyl, 4-(3-chloropropyl)-1-piperazinyl,4-(bromomethyl)-1-piperazinyl, 4-(2-fluoroethyl)-1-piperazinyl,4-(4-chlorobutyl)-1-piperazinyl, 4-(3-fluoropentyl)-1-piperazinyl,4-(2,3-dichlorohexyl)-1-piperazinyl,4-(2,2,2-trifluoroethyl)-1-piperazinyl,4-(trifluoromethyl)-1-piperazinyl, 4-aminomethyl-1-piperazinyl,4-(3-dimethylaminopropyl)-1-piperazinyl,4-(2-ethylaminoethyl)-1-piperazinyl,4-(4-propylaminobutyl)-1-piperazinyl,4-(5-n-butylaminopentyl)-1-piperazinyl,4-(6-pentylaminohexyl)-1-piperazinyl,4-(N-methyl-N-ethylaminomethyl)-1-piperazinyl,4-(N-methyl-N-propylaminomethyl)-1-piperazinyl,4-(2-diethylaminoethyl)-1-piperazinyl, 4-(methoxymethyl)-1-piperazinyl,4-(ethoxymethyl)-1-piperazinyl, 4-(2-propoxyethyl)-1-piperazinyl,4-(3-butoxypropyl)-1-piperazinyl, 4-(4-pentyloxybutyl)-1-piperazinyl,4-(5-hexyloxypentyl)-1-piperazinyl, 4-(6-methoxyhexyl)-1-piperazinyl,4-propargyl-1-piperazinyl, 4-(2-butynyl)-1-piperazinyl,4-(3-butynyl)-1-piperazinyl, 4-(1-methyl-2-propynyl)- 1-piperazinyl,4-(2-pentynyl)-1-piperazinyl, 4-(2-hexynyl)-1-piperazinyl,4-ethynyl-1-piperazinyl, 4-vinyl-1-piperazinyl, 4-allyl-1-piperazinyl,4-(2-butenyl)-1-piperazinyl, 4-(3-butenyl)-1-piperazinyl,4-(1-methylallyl)-1-piperazinyl, 4-(2-pentenyl)-1-piperazinyl,4-(2-hexenyl)-1-piperazinyl, 2-oxo-1-piperazinyl, 3-oxo-1-piperazinyl,4-oxo-3-methyl-1-piperazinyl 4,4-dimethyl-1-piperazinyl,4-(2-pyridyl)-1-piperazinyl, 4-(3-pyridyl)-1-piperazinyl,4-(4-pyridyl)-1-piperazinyl, 4-carbamoyl-1-piperazinyl,4-dimethylaminocarbonyl-1-piperazinyl,4-ethylaminocarbonyl-1-piperazinyl, 4-propylaminocarbonyl-1-piperazinyl,4-butylaminocarbonyl-1-piperazinyl, 4-pentylaminocarbonyl-1-piperazinyl,4-hexylaminocarbonyl-1-piperazinyl,4-diethylaminocarbonyl-1-piperazinyl,4-(N-methyl-N-propylaminocarbonyl)-1-piperazinyl,4-methoxycarbonyl-1-piperazinyl, 4-ethoxycarbonyl-1-piperazinyl,4-propoxycarbonyl-1-piperazinyl, 4-tert-butoxycarbonyl-1-piperazinyl,4-pentyloxycarbonyl-1-piperazinyl, 4-hexyloxycarbonyl-1-piperazinyl,4-benzyloxycarbonyl-1-piperazinyl,4-(2-phenylethoxycarbonyl)-1-piperazinyl,4-(3-phenylpropoxycarbonyl)-1-piperazinyl,4-(4-phenylbutoxycarbonyl)-1-piperazinyl,4-(5-phenylpentyloxycarbonyl)-1-piperazinyl,4-(6-phenylhexyloxycarbonyl)-1-piperazinyl,4-(2-aminoacetyl)-1-piperazinyl, 4-(3-amino-propionyl)-1-piperazinyl,4-(4-aminobutyryl)-1-piperazinyl, 4-(5-aminopentanoyl)-1-piperazinyl,4-(6-aminohexanoyl)-1-piperazinyl,4-(2-benzyloxycarbonylaminoacetyl)-1-piperazinyl,4-[2-(2-phenylethoxycarbonylamino)acetyl]-1-piperazinyl, 4-[2-(3-phenylpropoxycarbonylamino)acetyl]-1-piperazinyl,4-[2-(4-phenylbutoxycarbonylamino)acetyl]-1-piperazinyl,4-methoxycarbonylmethyl-1-piperazinyl,4-ethoxycarbonylmethyl-1-piperazinyl,4-(2-ethoxycarbonylethyl)-1-piperazinyl,4-(3-propoxycarbonylpropyl)-1-piperazinyl,4-(4-butoxycarbonylbutyl)-1-piperazinyl,4-(5-pentyloxycarbonylpentyl)-1-piperazinyl,4-(6-hexyloxycarbonylhexyl)-1-piperazinyl,4-carbonylmethyl-1-piperazinyl, 4-(2-carboxyethyl)-1-piperazinyl,4-(3-carboxypropyl)-1-piperazinyl, 4-(4-carboxybutyl)-1-piperazinyl,4-(5-carboxypentyl)-1-piperazinyl, 4-(6-carboxyhexyl)-1-piperazinyl,4-(anilinocarbonylmethyl)-1-piperazinyl,4-(2-anilinocarbonylethyl)-1-piperazinyl,4-(3-anilinocarbonylpropyl)-1-piperazinyl,4-(4-anilinocarbonylbutyl)-1-piperazinyl,4-(5-anilinocarbonylpentyl)-1-piperazinyl,4-(6-anilinocarbonylhexyl)-1-piperazinyl,4-(3-carboxyacryloyl)-1-piperazinyl,4-(3-carboxy-2,3-dichloroacryloyl)-1-piperazinyl,4-methyl-1-piperidinyl, 4-ethyl-1-piperidinyl, 4-propyl-1-piperidinyl,4-n-butyl-1-piperidinyl, 4-pentyl-1-piperidinyl, 4-hexyl-1-piperidinyl,4-methoxy-1-piperidinyl, 4-ethoxy-1-piperidinyl,4-propoxy-1-piperidinyl, 4-n-butoxy-1-piperidinyl,4-pentyloxy-1-piperidinyl, 4-hexyloxy-1-piperidinyl,4-acetyloxy-1-piperidinyl, 4-propionyloxy-1-piperidinyl,4-butyryloxy-1-piperidinyl, 4-pentanoyloxy-1-piperidinyl,4-hexanoyloxy-1-piperidinyl, 4-methoxycarbonyloxy-1 -piperidinyl,4-ethoxycarbonyl-1-piperidinyl, 4-propoxycarbonyl-1-piperidinyl,4-n-butoxycarbonyl-1-piperidinyl, 4-pentyloxycarbonyl-1-piperidinyl,4-hexyloxycarbonyl-1-piperidinyl, 4-benzyl-1-piperidinyl,4-(2-phenylethyl)-1-piperidinyl, 4-(1-phenylethyl)-1-piperidinyl,4-(3-phenylpropyl)-1-piperidinyl, 4-(4-phenylbutyl)-1-piperidinyl,4-(5-phenylpentyl)-1-piperidinyl, 4-(6-phenylhexyl)-1-piperidinyl,4-hydroxy-1-piperidinyl, 3-hydroxy-1-piperidinyl,2-hydroxy-1-piperidinyl, 4-amino-1-piperidinyl, 3-amino-1-piperidinyl,2-amino-1-piperidinyl, 4-dimethylamino-1-piperidinyl,4-methylamino-1-piperidinyl, 3-ethylamino-1-piperidinyl,2-propylamino-1-piperidinyl, 4-n-butylamino-1-piperidinyl,3-pentylamino-1-piperidinyl, 4-hexylamino-1-piperidinyl,3-diethylamino-1-piperidinyl, 4-(N-methyl-N-propylamino)-1-piperidinyl,4-carbamoyl-1-piperidinyl, 3-carbamoyl-1-piperidinyl,3,5-dimethyl-1-piperidinyl, 2,5-dimethyl-1-piperidinyl,4-oxo-1-piperidinyl, 3-oxo-1-piperidinyl, 3-hydroxy-1-pyrrolidinyl,3-amino-1-pyrrolidinyl, 2-hydroxy-1-pyrrolidinyl,2-amino-1-pyrrolidinyl, 3-methylamino-1-pyrrolidinyl,3-dimethylamino-1-pyrrolidinyl, 2-ethylamino-1-pyrrolidinyl,3-propylamino-1-pyrrolidinyl, 2-n-butylamino-1-pyrrolidinyl,3-pentylamino-1-pyrrolidinyl, 2-hexylamino-1-pyrrolidinyl,3-diethylamino-1-pyrrolidinyl,3-(N-methyl-N-propylamino)-1-pyrrolidinyl,2-(N-ethyl-N-n-butylamino)-1-pyrrolidinyl, 3-acetylamino-1-pyrrolidinyl,3-propionylamino-1-pyrrolidinyl, 2-butyrylamino-1-pyrrolidinyl, 3-pentanoylamino-1-pyrrolidinyl, 2-hexanoylamino-1-pyrrolidinyl,3-hydroxymethyl-1-pyrrolidinyl, 2-(2-hydroxyethyl)-1-pyrrolidinyl,3-(3-hydroxypropyl)-1-pyrrolidinyl, 2-(4-hydroxybutyl)-1-pyrrolidinyl,3-(5-hydroxypentyl)-1-pyrrolidinyl, 3-(6-hydroxyhexyl)-1-pyrrolidinyl,3-aminomethyl-1-pyrrolidinyl, 3-(2-aminoethyl)-1-pyrrolidinyl,2-(3-aminopropyl)-1-pyrrolidinyl, 3-(4-aminobutyl)-1-pyrrolidinyl,3-(5-aminopentyl)-1-pyrrolidinyl, 3-(6-aminohexyl)-1-pyrrolidinyl,3-(methylaminomethyl)-1-pyrrolidinyl,3-(2-ethylaminoethyl)-1-pyrrolidinyl,3-(3-propylaminopropyl)-1-pyrrolidinyl,2-(4-n-butylaminobutyl)-1-pyrrolidinyl,3-(5-pentylaminopentyl)-1-pyrrolidinyl,3-(6-hexylaminohexyl)-1-pyrrolidinyl,3-(dimethylaminomethyl)-1-pyrrolidinyl,2-(N-methyl-N-ethylaminomethyl)-1-pyrrolidinyl,3-(N-ethyl-N-n-butylaminomethyl)-1-pyrrolidinyl,3-methylaminomethyl-4-methyl-1-pyrrolidinyl,3-methylaminomethyl-4-fluoro-1-pyrrolidinyl,3-methylamino-4-methyl-1-pyrrolidinyl,3-methylamino-4-chloro-1-pyrrolidinyl,3-methylaminomethyl-4-chloro-1-pyrrolidinyl,3-methylamino-4-fluoro-1-pyrrolidinyl,3-ethylaminomethyl-4-ethyl-1-pyrrolidinyl,4-propylaminomethyl-2-propyl-1-pyrrolidinyl,4-n-butylaminomethyl-2-fluoro-1-pyrrolidinyl,4-pentylaminomethyl-2-n-butyl-1-pyrrolidinyl,4-hexylaminomethyl-2-chloro-1-pyrrolidinyl,4-propylamino-2-chloro-1-pyrrolidinyl,4-n-butylamino-2-hexyl-1-pyrrolidinyl,3-pentylamino-4-ethyl-1-pyrrolidinyl,3-hexylamino-4-fluoro-1-pyrrolidinyl, 4-methyl-1-homopiperazinyl,4-ethyl-1-homopiperazinyl, 4-propyl-1-homopiperazinyl, 4-n-butyl-1-homopiperazinyl, 4-pentyl-1-homopiperazinyl,4-hexyl-1-homopiperazinyl, 4-formyl-1-homopiperazinyl,4-acetyl-1-homopiperazinyl, 4-propionyl-1-homopiperazinyl,4-butyryl-1-homopiperazinyl, 4-pentanoyl-1-homopiperazinyl,4-hexanoyl-1-homopiperazinyl, 2-methyl-1-hexahydropyridazyl,2-ethyl-1-hexahydropyridazyl, 2-propyl-1-hexahydropyridazyl,2-n-butyl-1-hexahydropyridazyl, 2-pentyl-1-hexahydropyridazyl,2-hexyl-1-hexahydropyridazyl, 2-formyl-1-hexahydropyridazyl,2-acetyl-1-hexahydropyridazyl, 2-propionyl-1-hexahydropyridazyl,2-butyryl-1-hexahydropyridazyl, 2-pentanoyl-1-hexahydropyridazyl,2-hexanoyl-1-hexahydropyridazyl, 2-methyl-1-pyrazolidinyl,2-ethyl-1-pyrazolidinyl, 2-propyl-1-pyrazolidinyl,2-n-butyl-1-pyrazolidinyl, 2-pentyl-1-pyrazolidinyl,2-hexyl-1-pyrazolidinyl, 2-formyl-1-pyrazolidinyl,2-acetyl-1-pyrazolidinyl, 2-propionyl-1-pyrazolidinyl,2-butyryl-1-pyrazolidinyl, 2-pentanoyl-1-pyrazolidinyl,2-hexanoyl-1-pyrazolidinyl, 3,5-dimethylmorpholino, 3-methylmorpholino,3-ethylmorpholino, 2-propylmorpholino, 3-n-butylmorpholino,3-pentyl-5-methylmorpholino, 3-hexyl-5-ethylmorpholino,3-aminomethylmorpholino, 3-methylaminomethylmorpholino,2-ethylaminomethylmorpholino, 3-propylaminomethylmorpholino,3-n-butylaminomethylmorpholino, 2-pentylaminomethylmorpholino,3-hexylaminomethylmorpholino, 3-(2-methylaminoethyl)-morpholino,3-(3-methylaminopropyl)morpholino, 3-(4-methylaminobutyl)morpholino,2-(5-methylaminopentyl)-morpholino, 3-(6-methylaminohexyl)morpholino,4-(5-methyl-2-oxo-1,3 -dioxolen-4-yl)methyl-1-piperazinyl,4-(5-tert-butyl-2-oxo-1,3-dioxolen-4-yl)methyl-1-piperazinyl,4-(5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl-1-piperazinyl,4-(2-oxo-1,3-dioxolen-4-yl)methyl-1-piperazinyl,3-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methylamino-1-pyrrolidinyl,4-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methylamino-1-piperidinyl,3-(5-phenyl-2-oxo-1,3-dioxolen-4-yl)methylaminomorpholino,3,5-dimethyl-1-piperazinyl, 3,3-dimethyl-1-piperazinyl,4-acetyl-3-methyl-1-piperazinyl, 3-ethyl-1-piperazinyl,3-ethyl-4-methyl-1-piperazinyl, 3-trifluoromethyl-1-piperazinyl,3-(fluoromethyl)-1-piperazinyl, 3-methylthio-1-piperazinyl,4-methylthio-1-piperazinyl, 3-ethylthio-1-piperazinyl,3-methylthiomorpholino, 4-fluoro-1-piperidinyl, 3-fluoro-1-piperazinyl,3-chloro-1-piperazinyl, 3-amino-4-fluoro-1-pyrrolidinyl,3-amino-4-hydroxy-1-pyrrolidinyl, 3-amino-4-methoxy-1-pyrrolidinyl,3-amino-4-fluoro-1-piperidinyl, 3-amino-4-hydroxy-1-piperidinyl,3-amino-4-methyl-1-pyrrolidinyl, 4-benzyl-3-methyl-1-piperazinyl,3-fluoromethylmorpholino, 3-chloromethylmorpholino, 4-oxo-1-piperidinyl,3-oxo-1-piperidinyl, 2-oxo-1-piperidinyl,3-acetylaminomethyl-1-pyrrolidinyl,3-(N-ethyl-N-acetylamino)-methyl-1-pyrrolidinyl,3-t-butoxycarbonylaminomethyl-1-pyrrolidinyl,3-ethylaminomethyl-1-pyrrolidinyl, 4-cyclopropylamino-1-piperazinyl,3-cyclopropylamino-1-pyrrolidinyl, 4-cyclopentylamino-1-piperazinyl,4-cyclohexylamino-1-piperazinyl, 3-cycloheptylamino-1-pyrrolidinyl,4-cyclooctylamino-1-piperidinyl, 4-cyclopropylamino-1-piperidinyl,3-cyclopropylaminomorpholino, 4-thio-1-piperidinyl,3-thio-1-piperazinyl, 3-thiomorpholino,4-cyclopropylaminomethyl-1-piperazinyl,3-cyclopropylaminomethyl-1-pyrrolidinyl,4-cyclopropylaminomethyl-1-piperidinyl,3-cyclopropylaminomethylmorpholino,4-(2-cyclopentylaminoethyl)-1-piperazinyl,4-(3-cyclohexylaminopropyl)-1-piperazinyl,3-(4-cyclobutylaminobutyl)-1-pyrrolidinyl,4-(5-cyclooctylaminopentyl)-1-piperidinyl,4-(6-cyclopropylaminohexyl)morpholino,3-acetylaminomethyl-1-pyrrolidinyl,4-(2-propionylaminoethyl)-1-piperazinyl,4-(3-butyrylaminopropyl)-1-piperidinyl,3-(4-pentanoylaminobutyl)morpholino,4-(5-hexanoylaminopentyl)-1-piperazinyl,3-(6-acetylaminohexyl)-1-pyrrolidinyl,4-(N-acetyl-N-ethylamino)methyl-1-piperazinyl,4-(N-cyclopropyl-N-acetylamino)methyl-1-pyrrolidinyl,4-(methoxycarbonylaminomethyl)-1-piperazinyl,4-(2-ethoxycarbonylaminoethyl)-1-piperidinyl,3-(3-propoxycarbonylaminopropyl)morpholino,3-(4-pentyloxycarbonylaminobutyl)-1-pyrrolidinyl,3-(5-hexyloxycarbonylaminopentyl)-1-pyrrolidinyl,4-(6-t-butoxycarbonylaminohexyl)-1-piperazinyl,3-(N-t-butoxycarbonyl-N-ethylaminomethyl)-1-pyrrolidinyl,3-(N-t-butoxycarbonyl-N-methylaminomethyl)-1-pyrrolidinyl,3-(N-t-butoxycarbonyl-N-cyclopropylaminomethyl)-1-pyrrolidinyl,4-(N-methoxycarbonyl-N-cyclopropylaminomethyl)-1-piperazinyl and4-(N-propoxycarbonyl-N-cyclohexylaminomethyl)-1-piperidinyl. The term "a5- to 9-membered saturated or unsaturated heterocyclic ring which may besubstituted" also includes the group represented by the formula:##STR8## wherein R^(a) is hydrogen atom or a (lower) alkyl, R^(b) ishydrogen atom, a (lower) alkyl, a (lower) alkanoyl, aphenyl(lower)alkyl, or a 2-oxo-1,3-dioxolenemethyl which is substitutedby a (lower) alkyl, and R^(c) is hydrogen atom or a (lower) alkyl; thegroup represented by the formula: ##STR9## wherein R^(d) is hydrogenatom or a (lower) alkyl, and R^(e) is hydrogen atom or a (lower) alkyl;the group represented by the formula: ##STR10## wherein R^(f) is anamino which may be substituted by 1 or 2 substituents selected from thegroup consisting of a (lower) alkyl and a (lower) alkoxycarbonyl, or aamino(lower)alkyl which may be substituted by 1 or 2 substituentsselected from the group consisting of a (lower) alkyl and a (lower)alkoxycarbonyl, R^(g) is hydrogen atom or a (lower) alkyl; the grouprepresented by the formula: ##STR11## wherein R^(h) is hydrogen atom ora (lower) alkyl, R^(i) is hydrogen atom, hydroxy, a halogen atom or oxo,and R^(j) is hydrogen atom or a (lower) alkyl; and the like.

The term "a cycloalkyl" includes C₃ -C₈ cycloalkyl such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

The term "a phenyl (lower) alkyl in which phenyl ring may be substitutedby a (lower) alkoxy, nitro or amino" includes phenylalkyl in whichphenyl ring may be substituted by a straight chain or branched chain C₁-C₆ alkoxy, nitro or amino and the alkyl moiety is a straight chain orbranched chain C₁ -C₆ alkyl, such as benzyl, 2-phenylethyl,1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl,1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl,2-methyl-3-phenylpropyl, 4-methoxybenzyl, 3-ethoxybenzyl,2-propoxybenzyl, 4-n-butoxybenzyl, 3-pentyloxybenzyl, 2-hexyloxybenzyl,4-nitrobenzyl, 3-nitrobenzyl, 4-aminobenzyl, 2-aminobenzyl,2-(4-methoxyphenyl)ethyl, 1-(3-ethoxyphenyl)ethyl,3-(2-propoxyphenyl)propyl, 4-(4-n-butoxyphenyl)butyl,5-(2-nitrophenyl)pentyl or 6-(3-aminophenyl)hexyl.

The term "a phenyl which may be substituted by a halogen atom or a(lower) alkyl which may be substituted by 1 to 3 of halogen atoms"includes phenyl in which the phenyl ring may be substituted by a halogenatom or by a straight chain or branched chain C₁ -C₆ alkyl which may besubstituted by 1 to 3 of halogen atoms, such as phenyl, 4-fluorophenyl,-bromophenyl, 2-chlorophenyl, 4-iodophenyl, 4-methylphenyl,-ethylphenyl, 2-propylphenyl, 4-n-butylphenyl, 3-pentylphenyl,2-hexylphenyl, 4-trifluoromethylphenyl, 3-(2-chloroethyl)phenyl,2-(3,3-dibromopropyl)phenyl, 4-(4-chlorobutyl)phenyl,3-(5-iodopentyl)phenyl, 4-(6-fluorohexyl)phenyl,2-(1,2,2-trifluoroethyl)phenyl or 4-(2,2,2-trifluoroethyl)phenyl.

The term "a (lower) alkyl having 1 to 3 of substituents selected fromthe group consisting of hydroxy, an amino which may be substituted by a(lower) alkyl, a (lower) alkanoyl, a cycloalkyl or a (lower)alkoxycarbonyl, a (lower) alkoxy and a halogen atom" includes a straightsubstituents selected from the group consisting of hydroxy; an aminowhich may be substituted by 1 or 2 substituents selected from the groupconsisting of a straight chain or branched chain C₁ -C₆ alkyl, astraight chain or branched chain C₁ -C₆ alkanoyl, a C₃ -C₈ cycloalkyland a straight chain or branched chain (C₁ -C₆)alkoxy-carbonyl; astraight chain or branched chain C₁ -C₆ alkoxy and a halogen atom, suchas hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl,4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl, 3-chloropropyl,bromomethyl, 2-fluoroethyl, 4-chlorobutyl, 3-fluoropentyl,2,3-dichlorohexyl, 2,2,2-trifluoroethyl, trifluoromethyl, aminomethyl,2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl,6-aminohexyl, 3-dimethylaminopropyl, 2-ethylaminoethyl,4-propylaminobutyl, 5-n-butylaminopentyl, 6-pentylaminohexyl,methylaminomethyl, diethylaminomethyl, 2-dipropylaminoethyl,1-di-n-butylaminoethyl, 3-dipentylaminopropyl, 4-dihexylaminobutyl,N-methyl-N-ethylaminomethyl, N-methyl-N-propylaminomethyl,methoxymethyl, ethoxymethyl, 2-propoxyethyl, 3-butoxypropyl,4-pentyloxybutyl, 5-hexyloxypentyl, 6-methoxyhexyl, propoxymetyl,1-ethoxyethyl, 2-hexyloxyethyl, formylaminomethyl, acetylaminomethyl,2-propanoylaminoethyl, 3-butyrylaminopropyl, 4-pentanoylaminobutyl,5-hexanoylaminopentyl, 6-acetylaminohexyl, propanoylaminomethyl,1-acetylaminoethyl, 2-hexanoylaminoethyl, N-acetyl-N-methylaminomethyl,N-acetyl-N-ethylaminomethyl, N-acetyl-N-cyclopropylaminomethyl,N,N-dicyclopropylaminomethyl, cyclopropylaminomethyl,2-cyclobutylaminoethyl, 3-cyclopentylaminopropyl,1-cyclopropylaminoethyl, 2-cyclopropylaminoethyl, aminopropyl,4-cyclohexylaminobutyl, 5-cycloheptylaminopentyl,6-cyclooctylaminohexyl, N-methyl-N-cyclopropylaminomethyl,N-ethyl-N-cyclopropylaminomethyl, methoxycarbonylaminomethyl,2-ethoxycarbonylaminoethyl, 3-propoxycarbonylaminopropyl,4-t-butoxycarbonylaminobutyl, 5-pentyloxycarbonylaminopentyl,6-hexyloxycarbonylaminohexyl, t-butoxycarbonylaminomethyl,2-t-butoxycarbonylaminoethyl, 1-t-butoxycarbonylaminoethyl,N-t-butoxycarbonyl-N-methylaminomethyl,N-t-butoxycarbonyl-N-ethylaminomethyl orN-t-butoxycarbonyl-N-cyclopropylaminomethyl.

The term "a (lower) alkanoyl which may be substituted by 1 to 7 ofhalogen atoms" includes a straight chain or branched chain C₁ -C₆alkanoyl which may be substituted by 1 to 7 of halogen atoms, suchformyl, acetyl, propionyl, butyryl, pentanoyl, hexanoylα,α,α-trifluoroacetyl, β,β,β-trifluoro-α,α-difluoronyl,γ,γ,γ-trifluoro-β,β-difluoro-α,α-difluorobutyryl, α,α-dichloroacetyl,α-bromoacetyl, α-iodoacetyl, β-fluoropropionyl,β-fluoro-α-fluoropropionyl, 6-fluorohexanoyl or 4-chloropentanoyl,3,3,3-trifluoropropionyl.

The term "a (lower) alkenylcarbonyl having 1 to 3 substituents selectedfrom the group consisting of a halogen atom and a carboxy" includes astraight chain or branched chain (C₂ -C₆)alkenyl-carbonyl having 1 to 3of substituents selected from the group consisting of a halogen atom anda carboxy, such as 3-carboxyacryloyl, 3-carboxy-2,3-dichloroacryloyl,3-carboxy-2,3-dibromoacryloyl, 4-carboxycrotonoyl,4-carboxyisocrotonoyl, 5-carboxy-3-pentenoyl, 6-carboxy-4-hexenoyl,4-carboxy-3-fluorocrotonoyl or 5-carboxy-3,4-dichloro-3-hexenoyl.

The term "a (lower) alkoxycarbonyl" includes a straight chain orbranched chain (C₁ -C₆)alkoxy-carbonyl, such as methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,tert-butoxycarbonyl, pentyloxycarbonyl or hexyloxycarbonyl.

The term "an aminocarbonyl which may be substituted by a (lower) alkyl"includes aminocarbonyl which may be substituted by 1 or 2 of a straightchain or branched chain C₁ -C₆ alkyl, such as carbamoyl,methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl,n-butylaminocarbonyl, pentylaminocarbonyl, hexylaminocarbonyl,dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl,dipentylaminocarbonyl, dihexylaminocarbonyl,N-methyl-N-propylaminocarbonyl, N-methyl-N-tert-butylaminocarbonyl orN-ethyl-N-pentylaminocarbonyl.

The term "a phenyl(lower)alkoxycarbonyl" includes phenylalkoxycarbonylin which the alkoxy moiety is a straight chain or branched chain C₁ -C₆alkoxy, such as benzyloxycarbonyl, 2-phenylethoxycarbonyl,1-phenylethoxycarbonyl, 3-phenylpropoxycarbonyl, 4-phenylbutoxycarbonyl,1,1-dimethyl-2-phenylethoxycarbonyl, 5-phenylpentyloxycarbonyl,6-phenylhexyloxycarbonyl or 2-methyl-3-phenylpropoxycarbonyl.

The term "an amino(lower)alkanoyl which may be substituted by aphenyl(lower)alkoxycarbonyl" includes a straight chain or branched chainC₂ -C₆ aminoalkanoyl which may be substituted by a phenylalkoxycarbonylin which alkoxy moiety is a straight chain or branched chain C₁ -C₆alkoxy, such as 2-aminoacetyl, 3-aminopropionyl, 4-aminobutyryl,5-aminopentanoyl, 6-aminohexanoyl, 2-benzyloxycarbonylaminoacetyl,2-(2-phenylethoxycarbonylamino)acetyl,2-(3-phenylpropoxycarbonylamino)acetyl,3-(4-phenylbutoxycarbonylamino)propionyl,4-(1,1-dimethyl-2-phenylethoxycarbonylamino)butyryl,5-(5-phenylpentyloxycarbonylamino)pentanoyl,6-(6-phenylhexyloxycarbonylamino)hexanoyl or2-(2-methyl-3-phenylpropoxycarbonylamino)acetyl.

The term "a (lower) alkoxycarbonyl(lower)alkyl" includesalkoxycarbonylalkyl in which the alkoxy and alkyl moieties are astraight chain or branched chain C₁ -C₆ alkoxy and alkyl, respectively,such as methoxycarbonylmethyl, ethoxycarbonylmethyl,2-ethoxycarbonylethyl, 3-propoxycarbonylpropyl, 4-butoxycarbonylbutyl,5-pentyloxycarbonylpentyl, 6-hexyloxycarbonylhexyl,2-methoxycarbonylethyl, 3-methoxycarbonylpropyl, 3-ethoxycarbonylpropylor 4-ethoxycarbonybutyl.

The term "a carboxy(lower)alkyl" includes carboxyalkyl in which thealkyl moiety is a straight chain or branched chain C₁ -C₆ alkyl, such ascarboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl,5-carboxypentyl, 6-carboxyhexyl, 1-carboxyethyl,1,1-dimethyl-2-carboxyethyl or 2-methyl-3-carboxypropyl.

The term "an anilinocarbonyl(lower)alkyl" includes anilinocarbonylalkylin which the alkyl moiety is a straight chain or branched chain C₁ -C₆alkyl, such as anilinocarbonylmethyl, 2-anilinocaronylethyl,1-anilinocarbonylethyl, 3-anilinocarbonylpropyl, 4-anilinocarbonylbutyl,5-anilinocarbonylpentyl, 6-anilinocarbonylhexyl,1,1-dimethyl-2-anilinocarbonylethyl or 2-methyl-3-anilinocarbonylpropyl.

The term "an amino which may be substituted by a (lower) alkyl, a(lower) alkanoyl, a (lower) alkoxycarbonyl or a phenyl(lower)alkyl"includes amino which may be substituted by 1 or 2 of a straight chain orbranched chain C₁ -C₆ alkyl, a straight chain or branched chain C₁ -C₆alkanoyl, a straight chain or branched chain (C₁ -C₆)alkoxycarbonyl or aphenylalkyl in which alkyl moiety is a straight chain or branched chainC₁ -C₆ alkyl, such as amino, methylamino, ethylamino, propylamino,t-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino,di-n-propylamino, di-n-butylamino, dipentylamino, dihexylamino,N-methyl-N-n-butylamino, N-methyl-N-pentylamino, N-ethyl-N-hexylamino,acetylamino, formylamino, propionylamino, butyrylamino, pentanoylamino,hexanoylamino, N-methyl-N-acetylamino, N-ethyl-N-propionylamino,N-methyl-N-butyrylamino, N-n-propyl-N-pentanoylamino,N-ethyl-N-hexanoylamino, methoxycarbonylamino, ethoxycarbonylamino,propoxycarbonylamino, t-butoxycarbonylamino, pentyloxycarbonylamino,hexyloxycarbonylamino, butoxycarbonylamino,N-t-butoxycarbonyl-N-methylamino, N-t-butoxycarbonyl-N-ethylamino,N-t-butoxycarbonyl-N-benzylamino, benzylamino, (2-phenylethyl)amino,(1-phenylethyl)amino, (3-phenylpropyl)amino, (4-phenylbutyl)amino,(5-phenylpentyl)amino or (6-phenylhexyl)amino.

The term "a 2(5H)-furanone which may be substituted by 1 or 2 of halogenatoms" includes 2(5H)-furanone which may be substituted by 1 or 2 ofhalogen atoms, such as 2(5H)-furanon-5-yl,3,4-dibromo-2(5H)-furanon-5-yl, 3,4-dichloro-2(5H)-furanon-5-yl,3-chloro-2(5H)-furanon-5-yl, 4-fluoro-2(5H)-furanon-5-yl or3-iodo-2(5H)-furanon-5-yl.

The term "a sulfo(lower)alkyl" includes sulfoalkyl in which alkyl moietyis a straight chain or branched chain C₁ -C₆ alkyl, such as sulfomethyl,2-sulfoethyl, 1-sulfoethyl, 3-sulfopropyl, 4-sulfobutyl, 5-sulfopentyl,6-sulfohexyl, 1,1-dimethyl-2-sulfoethyl or 2-methyl-3-sulfopropyl.

The term "a (lower) alkylsulfonyl which may be substituted by 1 to 3 ofhalogen atoms" includes a straight chain or branched chain C₁ -C₆alkylsulfonyl which may be substituted by 1 to 3 of halogen atoms, suchas methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, n-butylsulfonyl,pentylsulfonyl, hexylsulfonyl, trifluoromethylsufonyl,2-fluoroethylsulfonyl, 3-fluoropropylsulfonyl,4,4,4-trifluorobutylsulfonyl, 5-chloropentylsulfonyl,6-bromohexylsulfonyl, 6-iodohexylsulfonyl, 2,2-difluoroethylsulfonyl or2,3-dibromopropylsulfonyl.

The term "a (lower) alkoxy" includes a straight chain or branched chainC₁ -C₆ alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy,tert-butoxy, pentyloxy or hexyloxy.

The term "a (lower) alkanoyloxy" includes a straight chain or branchedchain C₂ -C₆ alkanoyloxy, such as acetyloxy, propionyloxy, butyryloxy,isobutyryloxy, pentanoyloxy or hexanoyloxy.

The term "a (lower) alkenyl" includes a straight chain or branched chainC₂ -C₆ alkenyl, such as vinyl, allyl, 2-butenyl, 3-butenyl,1-methylallyl, 2-pentenyl or 2-hexenyl.

The term "a (lower) alkynyl" includes a straight chain or branched chainC₂ -C₆ alkynyl, such as ethynyl, 2-propynyl, 2-butynyl, 3-butynyl,1-methyl-2-propynyl, 2-pentynyl or 2-hexynyl.

The term "a 2-oxo-1,3-dioxolenemethyl which may be substituted by phenylor a (lower) alkyl" includes 2-oxo-1,3-dioxolenemethyl which may besubstituted by phenyl or a straight chain or branched chain C₁ -C₆alkyl, such as (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl,(5-tert-butyl-2-oxo-1,3-dioxolen-4-yl)methyl,(5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl,(2-oxo-1,3-dioxolen-4-yl)methyl,(5-pentyl-2-oxo-1,3-dioxolen-4-yl)methyl,(5-hexyl-2-oxo-1,3-dioxolen-4-yl)methyl,(5-ethyl-2-oxo-1,3-dioxolen-4-yl)methyl or(5-propyl-2-oxo-1,3-dioxolen-4-yl)methyl.

The term "a 2-oxo-1,3-dioxolenemethylamino which may be substituted byphenyl or a (lower) alkyl" includes 2-oxo-1,3-dioxolenemethylamino whichmay be substituted by phenyl or a straight chain or branched chain C₁-C₆ alkyl, such as (5-methyl-2-oxo-1,3-dioxolen-4-yl)methylamino,(5-tert-butyl-2-oxo-1,3-dioxolen-4-yl)methylamino,(5-phenyl-2-oxo-1,3-dioxolen-4-yl)methylamino,(2-oxo-1,3-dioxolen-4-yl)methylamino,(5-pentyl-2-oxo-1,3-dioxolen-4-yl)methylamino,(5-hexyl-2-oxo-1,3-dioxolen-4-yl)methylamino,(5-ethyl-2-oxo-1,3-dioxolen-4-yl)methylamino, or(5-propyl-2-oxo-1,3-dioxolen-4-yl)methylamino.

The term "a cycloalkylamino" includes C₃ -C₈ cycloalkylamino, such ascyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino,cycloheptylamino or cyclooctylamino.

The term "a (lower) alkylthio" includes a straight chain or branchedchain C₁ -C₆ alkylthio, such as methylthio, ethylthio, propylthio,isopropylthio, butylthio, tertbutylthio, penthylthio or hexylthio.

The term "a phenyl which may be substituted by 1 to 3 of substituentsselected from the group consisting of a (lower) alkoxy, a halogen atomand hydroxy on phenyl ring" includes phenyl which may be substituted by1 to 3 of substituents selected from the group consisting of a straightchain or branched chain C₁ -C₆ alkoxy, a halogen atom and hydroxy onphenyl ring, such as phenyl, 4-methoxyphenyl, 3-ethoxyphenyl,2-propoxyphenyl, 4-n-butoxyphenyl, 3-pentyloxyphenyl, 2-hexyloxyphenyl,3,4-dimethoxyphenyl, 2,4,6-trimethoxyphenyl, 2-fluorophenyl,4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-bromophenyl,2-iodophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,3,4-difluorophenyl, 2,5-difluorophenyl, 2,4-dichlorophenyl,2,6-dibromophenyl, 2,4,6-trifluorophenyl, 3,4,6-trichlorophenyl,4-fluoro-2-methoxyphenyl, 2-fluoro-4-hydroxyphenyl, 2-hydroxyphenyl,3-hydroxyphenyl, 4-hydroxyphenyl, 2,3-dihydroxyphenyl,2,4-dihydroxyphenyl or 2,4,6-trihydroxyphenyl.

The term "a (lower) alkyl which may be substituted by a halogen atom, a(lower) alkanoyloxy or hydroxy" includes, in addition to theabove-mentioned (lower) alkyl, a straight chain or branched chain C₁ -C₆alkyl which is substituted by 1 to 3 of substituents selected from thegroup consisting of a halogen atom, a straight chain or branched chainC₂ -C₆ alkanoyloxy or hydroxy, such as hydroxymethyl, 2-hydroxyethyl,1-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl,6-hydroxyhexyl, 3-chloropropyl, bromomethyl, 2-fluoroethyl,4-chlorobutyl, 3-fluoropentyl, difluoromethyl, 2,3-dichlorohexyl,2,2,2-trifluoroethyl, trifluoromethyl, acetyloxymethyl,2-propionyloxyethyl, 3-butyryloxypropyl, 4-pentanoyloxybutyl,5-hexanoyloxypentyl, 6-acetyloxyhexyl, propanoyloxymethyl,1-acetyloxyethyl, 2-acetyloxyethyl or 2-hexanoyloxyethyl.

The compounds of the present invention of the above general formula [1]can be prepared by various processes and preferably prepared, forexample, by the processes as shown in the following reaction schemes.##STR12## wherein R¹, R², R³ and X are as defined above, R^(2') is ahalogen atom or the R² group (R² is as defined above), R⁵ is a group ofthe formula: --COR¹⁰ (wherein R¹⁰ is a (lower) alkyl) or a group of theformula: --COOR¹¹ (wherein R¹¹ is a (lower) alkyl), R⁶ is a (lower)alkyl, R⁷ is a group of the formula: ##STR13## (wherein R¹² and R¹³ areeach a (lower) alkyl) or a (lower) alkoxy, X² and X³ are each a halogenatom, R⁸ and R⁹ are each a (lower) alkyl.

The halogenation of the compound [2] is carried out by reacting with ahalogenating agent in the presence or absence of a solvent. The solventincludes aromatic hydrocarbons such as benzene, toluene and xylene,halogenated hydrocarbons such as dichloromethane, chloroform and carbontetrachloride, ethers such as dioxane, tetrahydrofuran and diethylether, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and the like.The halogenating agent may be any conventional halogenating agents whichcan convert hydroxy in carboxy group into a halogen atom, and includes,for example, thionyl chloride, phosphorus oxychloride, phosphorusoxybromide, phosphorus pentachloride, phosphorus pentabromide, and thelike. The amounts of the compound [2] and the halogenating agent are notparticularly limited, but, in case of using no solvent, the halogenatingagent is usually used in a large excess amount, and in case of using asolvent, the halogenating agent is usually used in an amount of at least1 mole, preferably 2 to 4 moles, per 1 mole of the compound [2]. Thereaction temperature and the reaction period of time are notparticularly limited either, but the reaction is usually carried out ata temperature of from room temperature to around 100° C. for about 30minutes to about 6 hours.

The reaction between the compound [3] and the compound [4] is carriedout in a suitable solvent in the presence of a basic compound. Thesolvent used in the reaction may be any conventional solvents unlessthey give any undesirable effect on the reaction, and includes, forexample, water, ethers such as diethyl ether, dioxane, tetrahydrofuran,monoglyme and diglyme, alcohols such as methanol, ethanol andisopropanol, aromatic hydrocarbons such as benzene, toluene and xylene,aliphatic hydrocarbons such as n-hexane, heptane, cyclohexane andligroin, amines such as pyridine and N,N-dimethylaniline, halogenatedhydrocarbons such as chloroform, dichloromethane and carbontetrachloride, aprotic polar solvents such as DMF, DMSO andhexamethylphosphoramide (HMPA), and a mixture of these solvents. Thebasic compound employed in the reacion includes inorganic bases such asmetallic sodium, metallic potassium, metallic magnesium, sodium hydride,sodium amide, sodium hydroxide, potassium hydroxide, sodium carbonate,potassium carbonate and sodium hydrogen carbonate, metal alcoholatessuch as sodium methylate and sodium ethylate, and organic bases such aspyridine, piperidine, quinoline, triethylamine and N,N-dimethylaniline.The reaction is usually carried out at a temperature of from around 0°C. to around 150° C., preferably from around 0° C. to around 120° C.,for about 0.5 to about 20 hours. The compound [4] is usually used in anamount of at least 1 mole, preferably 1 to 2 moles, per 1 mole of thecompound [3]. The basic compound is usually used in an amount of atleast 1 mole, preferably 1 to 2 moles, per 1 mole of the compound [3].

The compound [5] wherein R⁵ is the group of the formula: --COR10 issubjected to the reaction for removal of the group: --COR10 in asuitable solvent in the presence of a basic compound. The solvent usedin the reaction includes, for example, ethers such as diethyl ether,dioxane, tetrahydrofuran, monoglyme and diglyme, aromatic hydrocarbonssuch as benzene, toluene and xylene, aliphatic hydrocarbons such asn-hexane, heptane and cyclohexane, aprotic polar solvents such as DMF,DMSO and HMPA, and the like. The basic compound includes ammonia gas,aqueous ammonia, ammonium salts such as ammonium chloride, primary orsecondary amines such as ethylamine, diethylamine and piperidine, andthe like. The reaction is usually carried out at a temperature of fromaround 0° C. to around 150° C., preferably from room temperature toaround 100° C., for about 1 to about 20 hours.

The compound [5] wherein R⁵ is a group of the formula: --COOR¹¹ issubjected to the reaction for removal of the group: --COOR¹¹ in anaqueous solution in the presence of an acid catalyst. The acid catalystused in the reaction includes mineral acids such as hydrochloric acidand sulfuric acid, and organic acids such as p-toluenesulfonic acid. Thereaction is usually carried out at a temperature of from around 0° C. toaround 150° C., preferably from room temperature to around 100° C., forabout 1 to about 20 hours.

The reaction between the obtained R⁵ group-removed compound and thecompound [6] is carried out in a suitable solvent. The solvent employedin the reaction may be any solvents which are used in the above reactionfor the removal of the R⁴ group in addition to anhydrous (lower)alkanoic acid such as acetic anhydride. The reaction is usually carriedout at a temperature of from around 0° C. to around 200° C., preferablyfrom around 0° C. to around 150° C., for about 0.5 to about 10 hours.The compound [6] is usually used in an equimolar to large excess amount,preferably in an equimolar to 2 times molar amount based on the compound[5]. In case of using a compound [6] wherein R⁷ is a (lower) alkoxygroup, the reaction may also be carried out by using acid anhydridessuch as acetic anhydride as a solvent as well as the above-mentionedsolvents at a temperature of from around 0° C. to around 200° C.,preferably from around 0° C. to around 170° C.

The reaction between the compound [7] and the compound [8] is carriedout in a suitable solvent. The solvent employed in the reaction may beany conventional solvents unless they give any undesirable effect on thereaction, and includes, for example, alcohols such as methanol, ethanoland propanol, ethers such as diethyl ether, dioxane, tetrahydrofuran,monoglyme and diglyme, aromatic hydrocarbons such as benzene, tolueneand xylene, aliphatic hydrocarbons such as n-hexane, heptane,cyclohexane and ligroin, halogenated hydrocarbons such as chloroform,methylene chloride and carbon tetrachloride, aprotic polar solvents suchas DMF, DMSO and HMPA, and the like. The reaction is usually carried outat a temperature of from around 0° C. to around 150° C., preferably fromroom temperature to around 100° C., for about 0.1 to about 15 hours. Thecompound [8] is usually used in an amount of at least 1 mole, preferably1 to 2 moles, per 1 mole of the compound [7]. In the reaction, a basiccompound may optionally be added. Such basic compound may be any basiccompounds which are used in the above reaction between the compound [3]and the compound [4].

The cyclization of the compound [9] is carried out in a suitable solventin the presence of a basic compound. The solvent employed in thereaction may be any conventional solvents unless they give anyundesirable effect on the reaction, and includes, for example, etherssuch as diethyl ether, dioxane, tetrahydrofuran, monoglyme and diglyme,aliphatic hydrocarbons such as n-hexane, heptane and ligroin,halogenated hydrocarbons such as chloroform, methylene chloride andcarbon tetrachloride, aprotic polar solvents such as DMF, DMSO and HMPA,and the like. The basic compound employed in the reaction includesinorganic bases such as metallic sodium, metallic potassium, sodiumhydride, sodium amide, sodium hydroxide, potassium hydroxide, sodiumcarbonate and potassium carbonate, metal alcoholates such as sodiummethylate and sodium ethylate, organic bases such as1,8-diazabicyclo[5.4.0]undecene-7 (DBU), N-benzyltrimethylammoniumhydroxide and tetrabutylammonium hydroxide, and the like. The reactionis usually carried out at a temperature of from around 0° C. to around200° C., preferably from room temperature to around 150° C., for about0.5 to about 15 hours. The basic compound is usually used in an amountof at least 1 mole, preferably 1 to 2 moles, per 1 mole of the compound[9].

The hydrolysis of the compound [1a] can be carried out under theconditions of conventional hydrolysis, for instance, in the presence ofa basic compound such as sodium hydroxide, potassium hydroxide, bariumhydroxide or potassium carbonate, a mineral acid such as sulfuric acid,hydrochloric acid or nitric acid, or an organic acid such as acetic acidor aromatic sulfonic acids, in a solvent including water, alcohols suchas methanol, ethanol and isopropanol, ketones such as acetone and methylethyl ketone, ethers such as dioxane and ethylene glycol diethyl ether,acetic acid, or a mixture thereof. The reaction is usually carried outat a temperature of from room temperature to around 200° C., preferablyfrom room temperature to around 150° C., for about 0.1 to about 30hours. By the reaction, there is produced the compound [1a']. ##STR14##wherein R¹, R², R³ and X are as defined above, X⁴ is a halogen atom, andR¹⁴ is hydrogen atom or a group of the formula: ##STR15## (wherein R¹⁵and R¹⁶ are each an alkyl).

For conducting the reaction between the compound [1b] and the compound[11], both compounds are used in a wide range of ratios, and thecompound [11] is usually used in an amount of at least 1 mole,preferably about 1 to about 5 moles, per 1 mole of the compound [1b].The reaction is carried out in an innert solvent, which includes, forexample, water, alcohols such as methanol, ethanol, isopropanol,butanol, amyl alcohol and isoamyl alcohol, aromatic hydrocarbons such asbenzene, toluene and xylene, ethers such as tetrahydrofuran, dioxane anddiglyme, dimethylacetamide, DMF, DMSO, HMPA, N-methylpyrrolidone, andthe like and a mixture thereof. Among these solvents, the preferred oneis DMF, DMSO, HMPA, and N-methylpyrrolidone. The reaction may also becarried out in the presence of an acid-removing agent, includinginorganic carbonates such as sodium carbonate, potassium carbonate,sodium hydrogen carbonate and potassium hydrogen carbonate and organicbases such as pyridine, quinoline and triethylamine. An alkaline methalhalide such as potassium fluoride may also be added to the reactionmixture. The reaction is usually carried out under a pressure of from 1to 20 atm., preferably from 1 to 10 atm., at a temperature of from roomtemperature to around 250° C., preferably from room temperature toaround 200° C., for about 10 minutes to about 30 hours.

The compound [1b'] wherein R¹⁴ is a group of the formula: ##STR16## canbe converted into the corresponding compound [1b'] wherein R¹⁴ ishydrogen atom by treating the former compound with an acid or a base todecompose the chelate compound. The acid employed in the reactionincludes mineral acids such as hydrochloric acid and sulfuric acid, andorganic acids such as acetic acid and p-toluenesulfonic acid. The baseemployed in the reaction includes mineral bases such as sodiumhydroxide, potassium hydroxide, sodium hydrogen carbonate, potassiumhydrogen carbonate and potassium carbonate, and organic bases such astriethylamine. The reaction favorably proceeds at a temperature of fromaround 0° C. to around 150° C., preferably from around 0° C. to around100° C. The acid or the base may be used in an amount of at least 1mole, preferably 1 to 10 moles, per 1 mole of the starting compound.##STR17## wherein X, R¹ and R³ are as defined above, either Z or W is--CH₂ -- and the other is --NH, n is an integer of 1 to 3, R17 is a(lower) alkyl; a cycloalkyl; a phenyl(lower)alkyl in which phenyl ringmay be substituted by a (lower) alkoxy, nitro or amino; a phenyl whichmay be substituted by a halogen atom or a (lower) alkyl which may besubstituted by 1 to 3 of halogen atoms; a pyridyl; a (lower) alkylhaving 1 to 3 of substituents selected from the group consisting ofhydroxy, an amino which may be substituted by 1 or 2 substituents of a(lower) alkyl, a (lower) alkanoyl, a cycloalkyl or a (lower)alkoxycarbonyl, a (lower) alkoxy and a halogen atom; a (lower) alkanoylwhich may be substituted by 1 to 7 of halogen atoms; a (lower)alkenylcarbonyl having 1 to 3 of substituents selected from the groupconsisting of a halogen atom and a carboxy; a (lower) alkoxycarbonyl; anaminocarbonyl which may be substituted by a (lower) alkyl; aphenyl(lower)alkoxycarbonyl; an amino(lower)alkanoyl which may besubstituted by a phenyl(lower)alkoxycarbonyl; a (lower)alkoxycarbonyl(lower)alkyl; a carboxy(lower)alkyl; ananilinocarbonyl(lower)alkyl; a (lower) alkylsulfonyl which may besubstituted by 1 to 3 of halogen atoms; a sulfo(lower)alkyl; a (lower)alkenyl or a (lower) alkynyl, X⁵ is a halogen atom, and either Z' or W'is --CH₂ -- and the other is --NR¹⁷.

The reaction between the compound [1c] and the compound [12] is carriedout in a suitable solvent in the presence of a hydrogen halide-removingagent. The solvent includes water, alcohols such as methanol, ethanoland isopropanol, ketones such as acetone and methyl ethyl ketone, etherssuch as diethyl ether and dioxane, aromatic hydrocarbons such asbenzene, toluene and xylene, and the like. The hydrogen halide-removingagent includes inorganic bases such as sodium hydroxide, potassiumhydroxide, sodium carbonate and potassium carbonate, alkaline metalssuch as sodium and potassium, and organic bases such as pyridine andpiperidine. If necessary, copper powders, copper halides such as copperiodide or alkaline metal halides such as sodium iodide and potassiumiodide may also be employed. The compound [12] is usually used in anequimolar to large excess amount, preferably 1 to 3 moles, per 1 mole ofthe compound [1c]. The reaction is usually carried out at a temperatureof from room temperature to around 150° C., preferably from around 50°C. to around 120° C., for about 1 to about 12 hours. ##STR18## whereinR¹, R³, Z, W, n and Z are as defined above, R¹⁸ and R¹⁹ are eachhydrogen atom or a lower alkyl, and either Z'' or W'' is --CH₂ -- andthe other is ##STR19##

The reaction between the compound [1c] and the compound [13] is carriedout in the presence or absence of a solvent in the presence of areducing agent. The solvent employed in the reaction includes, forexample, water, alcohols such as methanol, ethanol and isopropanol,lower alkanoic acids such as formic acid and acetic acid, ethers such asdioxane, diethyl ether, diglyme and tetrahydrofuran, aromatichydrocarbons such as benzen, xylene and toluene, and the like. Thereducing agent includes formic acid, alkaline metal or alkaline earthmetal salts of formic acid such as sodium formate, reducing agents forhydrogenation such as sodium borohydride, sodium cyanoborohydride andlithium aluminum hydride, catalysts for catalytic reduction such aspalladium black, palladium carbon, platinum oxide, platinum black andRaney nickel, and the like. In case of using formic acid as the reducingagent, the reaction is usually carried out at a temperature of from roomtemperature to around 200° C., preferably from around 50° C. to around150° C., for about 1 to about 10 hours. Formic acid is preferably usedin a large excess amount to the compound [1c]. Besides, in case of usinga reducing agent for hydrogenation, the reaction is usually carried outat a temperature of from around -30° C. to around 100° C., preferablyfrom around 0° C. to around 70° C., for about 30 minutes to about 12hours. The reducing agent is usually used in an amount of from 1 to 20moles, preferably from 1 to 6 moles, per 1 mole of the compound [1c]. Incase of using lithium aluminum hydride as the reducing agent, apreferable solvent includes ethers such as diethyl ether, dioxane,tetrahydrofuran and diglyme, aromatic hydrocarbons such as benzene,toluene and xylene, and the like. In case of using a catalyst forcatalytic reduction, the reaction is usually carried out under ahydrogen pressure of from ordinary pressure to 20 atm., preferably fromordinary pressure to 10 atm., at a temperature of from -30° C. to 100°C., preferably from 0° C. to 60° C., for 1 to 12 hours. The catalyst isusually used in an amount of from 0.1 to 40% by weight, preferably from0.1 to 20% by weight, of the compound [1c]. The compound [13] is usuallyused in an amount of at least 1 mole, preferably 1 moles to a largeexcess amount, per 1 mole of the compound [1c].

In the reaction scheme-II, the compounds of the formula [1b] wherein R¹⁴is a group: ##STR20## can be prepared, for example, by the process asshown in the following reaction scheme-V. ##STR21## wherein R¹, R³, X,X⁴, R¹⁵ and R¹⁶ are as defined above, R^(6') is a (lower) alkyl orhydrogen atom, R¹⁴ is a group: ##STR22## and R²⁰ is a (lower) alkyl.

The reaction between the compound [1f] and the compound [14] is carriedout in a suitable solvent. The solvent employed in the reactionincludes, for example, the solvents employed in the reaction between theR⁵ group-removed compound and the compound [6] in the above reactionscheme-I. The reaction is usually carried out at a temperature of fromroom temperature to around 200° C., preferably from room temperature toaround 150° C., for about 10 minutes to about 5 hours. The compound [14]is usually used in an amount of at least 1 mole, preferably 1 to 10moles, per 1 mole of the compound [1f].

The compounds [8] employed in the reaction scheme-I are novel or knowncompounds, which can be prepared, for example, by the process as shownin the following reaction scheme-VI. ##STR23## wherein X⁵ is a halogenatom, R²¹ is a phenyl(lower)alkyl, R²² is a phenyl(lower)alkoxycarbonyl,m is an integer of 1 to 3, M' is an alkaline metal such as sodium orpotassium, and M'' is hydrogen atom or M'.

The reaction between the compound [15Z] and the compound [16] can becarried out under reaction conditions usually employed in a reaction forforming an amide bond. For forming an amide bond, known reactionconditions for the amide bond formation can be employed, for example,(a) a mixed acid anhydride process: a process which comprises reactingthe carboxylic acid [15] with an alkyl halocarboxylate to give a mixedacid anhydride, which is then reacted with the azide [16]; (b) an activeester process: a process which comprises converting the carboxylic acid[15] into an active ester such as p-nitrophenyl ester,N-hydroxysuccinimide ester or 1-hydroxybenzotriazole ester, and thenreacting the resultant ester with the azide [16]; (c) a carbodiimideprocess: a process which comprises condensing the carboxylic acid [15]with the azide [16] in the presence of an activating agent such asdicyclohexylcarbodiimide or carbonyldiimidazole; and (d) otherprocesses: a process which comprises converting the carboxylic acid [15]into the carboxylic anhydride using a dehydration agent such as aceticanhydride, and then reacting the resultant anhydride with the azide[16], a process which comprises reacting an ester from the carboxylicacid [15] and a lower alcohol with the azide [16] under a high pressureat a high temperature, or a process which comprises reacting an acidhalide of the carboxylic acid [15], i.e. acyl halide with the azide[16].

The mixed acid anhydride used in the above mixed acid anhydride processcan be obtained by a conventional Schotten-Baumann reaction, and theresultant anhydride is reacted with the azide [16], usually withoutseparating it from the reaction mixture, to prepare the compound [17].The Schotten-Baumann reaction is carried out in the presence of a basiccompound. The basic compound which can be employed in the reactionincludes those usually employed in the Schotten-Baumann reaction, forexample, organic bases such as triethylamine, trimethylamine, pyridine,dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo [4,3,0] nonene-5(DBN), 1,8-diazabicyclo [5,4,0] undecene-7 (DBU) and 1,4-diazabicyclo[2,2,2] octane (DABCO), and inorganic bases such as potassium carbonate,sodium carbonate, potassium hydrogen carbonate and sodium hydrogencarbonate. The reaction is usually carried out at a temperature of fromaround -20° C. to around 100° C., preferably from around 0° C. to around50° C., for 5 minutes to 10 hours, preferably 5 minutes to 2 hours. Thereaction between the obtained mixed acid anhydride and the azide [16] isusually carried out at a temperature of from around -20° C. to around150° C., preferably from around 0° C. to around 50° C., for 5 minutes to10 hours, preferably for 5 minutes to 5 hours. The mixed acid anhydrideprocess is usually carried out in a solvent. The solvent may be anywhich is usually employed in the mixed acid anhydride process, includingwater, halogenated hydrocarbons such as methylene chloride, chloroformand dichloroethane, aromatic hydrocarbons such as benzene, toluene andxylene, ethers such as diethyl ether, tetrahydrofuran anddimethoxyethane, esters such as methyl acetate and ethyl acetate,ketones such as acetone, aprotic polar solvents such as DMF, DMSO andHMPA, and a mixture thereof. The alkyl halocarboxylate used in the mixedacid anhydride process includes, for example, methyl chloroformate,methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutylchloroformate, and the like. The azide [16] is usually used in an amountof at least 1 mole, preferably 1 to 1.5 moles, per 1 mole of thecarboxylic acid [15].

In case of using the process of reacting an acyl halide with the azide[16], the reaction is carried out in a suitable solvent in the presenceof a basic compound. The basic compound used in the reaction may be anyknown basic compounds, including, for example, sodium hydroxide,potassium hydroxide, sodium hydride, potassium hydride, silvercarbonate, and metal alcoholates such as sodium methylate and sodiumethylate, in addition to the basic compound employed in the aboveSchotten-Baumann reaction. The solvent used in the reaction includes,for example, alcohols such as methanol, ethanol, propanol, butanol,3-methoxy-1-butanol, ethyl cellosolve and methyl cellosolve, pyridine,acetone, acetonitrile, the solvents employed in the above mixed acidanhydride process, and a mixture thereof. Although the ratio of theazide [16] and an acyl halide employed is not particularly limited, theacyl halide is usually used in an amount of at least 1 mole, preferably1 to 5 moles, per 1 mole of the azide [16]. The reaction is usuallycarried out at a temperature of from around -30° to around 180° C.,preferably from around 0° C. to around 150° C., for about 5 minutes toabout 30 hours. The compound [17] thus prepared may be used in asubsequent reaction without separating it from the reaction mixture.

The reaction between the compound [17] and the compound [18] is usuallycarried out at a temperature of from around 0° C. to around 150° C.,preferably from room temperature to around 100° C., for 1 to 15 hours,in a suitable solvent or in the absence a solvent. The compound [18] isusually used in an amount of at least 1 mole, preferably 1 to 2 moles,per 1 mole of the compound [17].

The reaction of converting the compound [19] into the compound [20] canbe carried out under the same reaction conditions as used in thereaction for removing a phenyl (lower) alkyl or a phenyl (lower)alkoxycarbonyl on the heterocyclic ring attached to the above compound[1].

The reaction of directly converting the compound [15] into the compound[20] is generally referred to as Schmidt reaction, and carried out in asuitable solvent in the presence of an acid. The acid employed in thereaction includes mineral acids such as sulfuric acid and hydrochloricacid, phosphorus compounds such as phosphorus oxychloride, phosphoruspentachloride, phosphorus trichloride and phosphorus pentoxide, thionylchloride, iron [III] chloride, aluminum chloride, stannic chloride,sulfoacetic acid, phosphoric acid, and the like. The solvent includesaromatic hydrocarbons such as benzene, toluene and xylene, halogenatedhydrocarbons such as chloroform, dichloromethane and carbontetrachloride, and the like. The reaction is usually carried out at atemperature of from around 0° C. to around 150° C., preferably fromaround 0° C. to around 100° C., for about 0.5 to about 10 hours. Thecompound [16a] is usually used in an amount of at least 1 mole,preferably 1 to 2 moles, per 1 mole of the compound [ 15]. ##STR24##wherein R²³ is phenyl, a lower alkyl or hydrogen atom, X⁶ is a halogenatom, either Z"' or W"' is --CH₂ -- and the other is a group: ##STR25##and R¹, R³, Z, W, X and n are as defined above.

The reaction between the compound [1c] and the compound [21] can becarried out under the same reaction conditions as employed in thereaction between the compound [1b] and the compound [11] in the abovereaction scheme-II.

Among the compounds [1], the compound in which the heterocyclic ring issubstituted by (a) a phenyl(lower)alkyl in which phenyl ring may besubstituted by a (lower) alkoxy, nitro or amino; (b) a (lower) alkanoylwhich may be substituted by 1 to 7 of halogen atoms, a (lower)alkenylcarbonyl having 1 to 3 of substituents selected from the groupconsisting of a halogen atom and a carboxy; (c) a (lower)alkoxycarbonyl; (d) an aminocarbonyl which may be substituted by a(lower) alkyl; (e) a phenyl(lower)alkoxycarbonyl; (f) anamino(lower)alkanoyl which may be substituted by aphenyl(lower)alkoxycarbonyl; (g) phthalide; (h) a 2(5H)-furanone whichmay be substituted by 1 or 2 of halogen atoms; or (i) a2-oxo-1,3-dioxolenemethyl which may be substituted by phenyl or a(lower) alkyl can be converted into the compound [1] in which theheterocyclic ring is not substituted, for example, using the followingmethods.

The compound [1] in which the heterocyclic ring is substituted by (a) or(e) can be converted into the compound [1] in which the heterocyclicring is not substituted, by treating the former compound in a suitablesolvent such as, for example, water, a (lower) alcohol such as methanol,ethanol or isopropanol, an ether such as dioxane or tetrahydrofuran,acetic acid, or a mixture thereof, in the presence of a catalyst forcatalytic reduction such as palladium carbon or palladium black, under ahydrogen pressure of from 1 to 10 atom., at a temperature of from around0° C. to around 100° C., for about 0.5 to about 10 hours, wherein amineral acid such as hydrochloric acid may be added to the reactionmixture, or by heating the former compound in an aqueous hydrobromicacid solution, to remove the phenyl(lower)alkyl such as benzyl or thephenyl(lower)-alkoxycarbonyl.

The compound 1] in which the heterocyclic ring is substituted by any ofthe substituents (b) to (i) can be converted into the compound [1] inwhich the heterocyclic ring is not substituted, by hydrolyzing theformer compound under the same reaction conditions as employed in thehydrolysis of the above compound [1a].

The compound [1] in which the heterocyclic ring is substituted by aminocan be converted into the compound [1] in which the heterocyclic ring issubstituted by a group: ##STR26## by using the same reaction conditionsas employed in the reaction between the compound [1c] and the compound[21] in the above reaction scheme-VII. The compound [1] in which theheterocyclic ring is substituted by a group: ##STR27## can also beconverted into the compound [1] in which the heterocyclic ring issubstituted by amino, by hydrolyzing the former compound under the samereaction conditions as employed in the hydrolysis of the above compound[1a]. ##STR28## wherein R¹, R^(2'), R³ and X are as defined above, R²⁴,R²⁵, R²⁶, R²⁷ and R²⁸ are each a (lower) alkyl, and X⁷ is a halogenatom.

The reaction between the compound [22] and the compound [8] can becarried out under the same reaction conditions as employed in thereaction between the compound [1b] and the compound [11] in the abovereaction scheme-II.

The reaction between the compound [23] and the compound [24a] or [24b]is carried out in the presence or absence of a solvent, preferably inthe absence of a solvent. The solvent used in the reaction includes, forexample, alcohols such as methanol, ethanol and isopropanol, aromatichydrocarbons such as benzene and toluene, polar solvents such asacetonitrile, DMF, DMSO and HMPA, and the like. The compound [24a] or[24b] is usually used in an amount of at least 1 mole, preferably 1 to1.5 moles, per 1 mole of the compound [23]. The reaction is usuallycarried out at a temperature of from room temperature to around 200° C.,preferably from around 60° C. to around 200° C., for about 0.5 to about25 hours.

The cyclization of the compound [25] or [26] can be carried outaccording to various known methods for the cyclization, including aheating method, a method using an acidic compound such as phosphorusoxychloride, phosphorus pentachloride, phosphorus trichloride, thionylchloride, conc. sulfuric acid or polyphosphoric acid, and the like. Incase of using the heating method, the reaction is usually carried out ina high b.p. solvent such as a high b.p. hydrocarbon or a high b.p. ethersuch as tetralin, diphenyl ether or diethylene glycol dimethyl ether ata temperature of from 100° C. to 250° C., preferably from 150° C. to200° C. In case of using the method with an acidic compound, the acidiccompound is usually used in an equimolar to a large excess amount,preferably 10 to 20 moles, per 1 mole of the compound [25] or [26]. Thereaction is usually carried out in the presence or absence of a suitablesolvent at a temperature of from room temperature to 150° C. for about0.1 to about 6 hours. The solvent includes acid anhydrides such asacetic anhydride in addition to the solvents employed in the cyclizationof the above compound [9].

The hydrolysis of the compound [1i] can be carried out under the samereaction conditions as employed in the hydrolysis of the compound [1a]in the above reaction scheme-I.

The compound [1j] in which R^(2') is a 5- to 9-membered saturated orunsaturated heterocyclic ring having a (lower) alkoxycarbonyl on thesecondary nitrogen atom can be converted into the corresponding compoundin which R^(2') is a 5- to 9-membered saturated or unsaturatedheterocyclic ring having no substituent on the secondary nitrogen atomby treating the former compound under the same reaction conditions asemployed in the hydrolysis of the compound [1a] in the above reactionscheme-I.

The compound [22] employed as the starting material in the abovereaction scheme-VIII can be prepared, for example, by the processes asshown in the following reaction schemes-IX to XI. ##STR29## wherein R¹,R^(2'), R³, X, X⁵ and X⁷ are as defined above, and R²⁹ is a (lower)alkanoyl.

The reaction of converting the compound [27] to the compound [28√ can becarried out under the same reaction conditions as employed in thedesulfurization of the compound [41] or [45] in reaction scheme-X asdisclosed hereinafter.

The reaction of converting the compound [28] into the compound [29] iscarried out in the presence of a (lower) alkanoylating agent, whichincludes a (lower) alkanoic acid such as formic acid, acetic acid orpropionic acid, a (lower) alkanoic acid anhydride such as aceticanhydride, a (lower) alkanoic acid halide such as acetyl chloride orpropionyl bromide, or the like. In case of using an acid anhydride or anacid halide as the (lower) alkanoylating agent, a basic compound mayalso be employed. The basic compound includes, for example, alkalimetals such as metallic sodium and metallic potassium; hydroxides,carbonates or hydrogen carbonates of these alkali metals; organic basessuch as pyridine and piperidine, and the like. The reaction can becarried out in either the presence or the absence of a solvent, usuallyin the presence of a suitable solvent. The solvent includes, forexample, ketones such as acetone and methyl ethyl ketone, ethers such asdiethyl ether and dioxane, aromatic hydrocarbons such as benzene,toluene and xylene, acetic acid, acetic anhydride, water, pyridine, andthe like. The (lower) alkanoylating agent is used in an amount of atleast 1 mole per 1 mole of the compound [28], usually in an equimolar toa large excess amount. The reaction is usually carried out at atemperature of from around 0° C. to around 150° C., preferably fromaround 0° C. to around 100° C., for about 5 minutes to about 15 hours.In case of using a (lower) alkanoic acid as the (lower) alkanoylatingagent, a dehydrating agent is preferably employed, which includesmineral acids such as sulfuric acid and hydrochloric acid, sulfonicacids such as p-toluenesulfonic acid, benzenesulfonic acid andethanesulfonic acid and the like, and the reaction is preferably carriedout at a temperature of from around 50° C. to around 120° C.

The nitration of the compound [28] or [29] is carried out by treatingthe said compound with a nitrating agent such as fuming nitric acid,concd. nitric acid, a mixed acid (e.g. nitric acid plus sulfuric acid,fuming sulfuric acid, phosphoric acid or acetic anhydride, etc.), analkali metal nitrate plus sulfuric acid, an anhydride of nitric acid andan organic acid such as acetyl nitrate or benzoyl nitrate, nitrogentetraoxide, nitric acid plus mercury nitrate, nitrate of acetonecyanohydrin, an alkyl nitrate plus sulfuric acid or a polyphosphoricacid, without a solvent or in the presence of a solvent such as aceticacid, acetic anhydride or sulfuric acid. The nitrating agent ispreferably used in an amount of 1 to 5 moles per 1 mole of the compound[28] or [29]. The reaction is usually carried out at a temperature offrom around -10° C. to around 70° C. for about 10 minutes to about 24hours.

The hydrolysis of the compound [30] is carried out under the samereaction conditions as employed in the hydrolysis of the above compound[la].

The reaction of converting the compound [31] into the compound [22] canbe carried out by converting the former compound into a diazonium saltthereof using sodium nitrite and an acid such as sulfuric acid,hydrochloric acid hydrobromic acid or boron fluoride in a solvent suchas a (lower) alkanoic acid such as acetic acid or water, and thenreacting the diazonium salt with a copper powder or a copper halide suchas, for example, cuprous bromide, cuprous chloride or cupric chloride inthe presence of a hydrohalogenic acid such as, for example, hydrobromicacid or hydrochloric acid, or reacting with potassium iodide in thepresence or absence of a copper powder, preferably with a copper halidein the presence of a hydrohalogenic acid. The sodium nitrite is usuallyused in an amount of 1 to 2 moles, preferably 1 to 1.5 moles, per 1 moleof the compound [31], and the copper halide is usually used in an amountof 1 to 5 moles, preferably 1 to 4 moles, per 1 mole of the compound[22]. The reaction is usually carried out at a temperature of fromaround -20° C. to around 100° C., preferably from around -5° C. toaround 100° C., for about 10 minutes to about 5 hours.

The halogen atoms of R^(2') and X⁹ in the compound [22], the compound[1a], the compound [1a'] and the compound [33] described below can beconverted into each other. ##STR30## wherein R^(2'), X⁶ and X⁷ are asdefined above, R³⁰ is hydrogen atom or a (lower) alkyl, and R³¹ is a(lower) alkyl, and R³⁰ and R³¹ may combine together to form a 5- to7-membered ring. ##STR31## wherein R^(2'), X⁶, X⁷, R³⁰ and R³¹ are asdefined above.

The nitration of each compound [32], [35] or [42] can be carried outunder the same reaction conditions as employed in the nitration of thecompound [28] or [29].

The reduction of the compound [33] or [36] is usually carried out by (i)reducing the compound with a catalyst for catalytic reduction in asuitable solvent, or by (ii) reducing the compound with a reducing agentsuch as a mixture of metal or metal salt with an acid or a mixture ofmetal or metal salt with hydroxide, sulfide or ammonium salt of alkalimetal in a suitable innert solvent. In case of the process (i) of thecatalytic reduction, the solvent employed in the reaction includes, forexample, water, acetic acid, alcohols such as methanol, ethanol andisopropanol, hydrocarbons such as hexane and cyclohexane, ethers such asdiethylene glycol dimethyl ether, dioxane, tetrahydrofuran and diethylether, esters such as ethyl acetate and methyl acetate, aprotic polarsolvent such as N,N-dimethyl formamide, and the like. The catalyst forcatalytic reduction employed in the reaction includes, for example,palladium, palladium black, palladium carbon, platinum, platinum oxide,copper chromite, Raney nickel, and the like. The catalyst is usuallyused in an amount of from 0.02 to 1.00 times weight based on thecompound [33] or [36]. The reaction is usually carried out at atemperature of from around -20° C. to around 150° C., preferably fromaround 0 ° C. to room temperature at a hydrogen pressure of from 1 to 10atm. for about 0.5 to about 10 hours. In case of using the process (ii),the employed reducing agent includes a mixture of iron, zinc, tin or tin(II) chloride with a mineral acid such as hydrochloric acid or sulfuricacid, a mixture of iron, iron (II) sulfate, zinc or tin with alkalimetal hydroxide such as sodium hydroxide, sulfate such as ammoniumsulfate, aqueous ammonia or ammonium chloride, and the like. The innertsolvent includes, for example, water, acetic acid, methanol, ethanol,dioxane and the like. The reaction conditions of the above reduction mayvary depending on a kind of the reducing agent employed. For example,the reaction is advantageously carried out at a temperature of fromaround 0° C. to room temperature for about 0.5 to about 10 hours whenthe reducing agent is a combination of tin (II) chloride andhydrochloric acid. The reducing agent is usually employed in an amountof at least 1 mole, preferably 1 to 5 moles per 1 mole of the startingcompound.

In case that R³⁰ and R³¹ of the compound [40] or 44] are taken togetherto form a 5- to 7-membered ring, R³⁰ of the compound [41] or [45] is--R³⁰ --R³¹ -H.

The compound [40] or [44] can be prepared by reacting the startinganiline derivative of the formula [37] or [34] with a halogenating agentand then reacting the resultant compound of the formula [38] or [43]with the thio compound of the formula [39].

The reaction between the aniline derivative [37] or [34] and thehalogenating agent is usually carried out in a suitable solvent. Thesolvent may be any conventional solvents unless they give anyundesirable effect on the reaction. Such solvent includes, for example,halogenated hydrocarbons such as chloroform and dichloromethane, etherssuch as dioxane, diethyl ether and tetrahydrofuran, aromatichydrocarbons such as benzene, toluene and xylene, lower alcohols such asmethanol, ethanol and isopropanol, polar solvents such as DMSO, HMPA andacetonitrile, and the like. The halogenating agent employed in the abovereaction may be any conventional halogenating agents and includes, forexample, N-bromosuccinimide, N-chlorosuccinimide, sodium hypobromite,sodium hypochlorite, bleaching powder, thionyl chloride, tert-butylhypochloride, and the like. The halogenating agent is usually used in anamount of at least 1 mole, preferably 1 to 6 moles, per 1 mole of thestarting compound. The reaction is usually carried out at a temperatureof from around -78° C. to room temperature, preferably from around -60°C. to around 15° C., and usually completes in a moment or within a fewminutes.

By the reaction, there is produced the intermediate of the formula [38]or [43]. While the resultant compound [38] or [43] may be separated fromthe reaction mixture to provide it for a subsequent reaction, thereaction mixture is usually subjected to the reaction with the thiocompound of the formula [39] without separating it from the reactionmixture.

The reaction between the intermediate compound [38] or [43] and thecompound [39] is carried out in the same solvent and at the sametemperature as mentioned above in the presence of a suitable basiccompound. The preferable basic compound which can be employed in thereaction includes inorganic bases such as potassium carbonate, sodiumcarbonate, sodium hydroxide, sodium hydrogen carbonate, sodium amide andsodium hydride, and organic bases including tertiary amines such astriethylamine, tripropylamine, pyridine and quinoline. The compound [39]is usually used in an amount of at least 1 mole, preferably 1 to 1.5moles, per 1 mole of the intermediate compound [38] or [43]. Thereaction is usually carried out at a temperature of from roomtemperature to around 150° C., preferably from room temperature toaround 100° C., for about 1 to about 50 hours.

The desulfurization of the compound [40] or [44] for preparing thecompound [41] or [45] is usually carried out in a solvent in thepresence of a suitable catalyst. The catalyst includes, for example,aluminum-amalgam, lithium-(lower) alkylamine, Raney nickel, Raneycobalt, triethyl phosphite, triphenyl phosphine, and the like, andpreferably Raney nickel. The solvent includes alcohols such as methanol,ethanol and isopropanol, ethers such as diethyl ether, dioxane andtetrahydrofuran, and the like. The reaction is usually carried out at atemperature of from around 0° C. to around 200° C., preferably from roomtemperature to around 100° C., for about 10 minutes to about 5 hours.The catalyst is usually used in an amount of from 1 to 10-fold by weightof the compound [40] or [44].

The reaction of converting the compound [34] or [45] into the compound[35] or [42] respectively is carried out by reacting the startingcompound with nitrite of metal such as sodium nitrite or potassiumnitrite in a solvent such as water in the presence of an acid to give adiazonium salt, which is then heated at from around 150° C. to around200° C., or heated at from room temperature to around 150° C. in thepresence of copper (I) bromide - hydrobromic acid, copper (I) chloride -hydrochloric acid, hydrobromic acid, potassium iodide, or an acid suchas hydrochloric acid plus copper powder. The acid employed in thereaction includes, for example, hydrochloric acid, hydrobromic acid,sulfuric acid, tetrafluoroboric acid, hexafluorophosphoric acid, and thelike. The acid and the nitrate of metal are usually used in an amount offrom 1 to 5 moles, preferably from 1 to 3 moles, and of at least 1 mole,preferably from 1 to 1.5, moles, respectively, per 1 mole of thecompound [34] or [45]. The amount of the acid employed in heating theobtained diazonium salt is usually at least 1 moles, preferably from 1to 1.5 moles per 1 mole of the compound [34] or [46].

The deamination of the compound [41] to prepare the compound [42] iscarried out by, for example, reacting the compound [41] with t-butylnitrite in the presence of a suitable solvent. The solvent employed inthe reaction includes, for example, dimethyl formamide, dimethylsulfoxide, hexamethylphosphoric acid triamide, and the like. The t-butylnitrite is usually used in an amount of at least 1 mole, preferably from1 to 2 moles per 1 mole of the compound [41]. The reaction is usuallycarried out at a temperature of from room temperature to around 150° C.,preferably from room temperature to around 100° C. for about 0.1 to 5hours. ##STR32## wherein R^(2'), X, X⁵, X⁶, R³⁰ and R³¹ are as definedabove.

The reaction between the compound [46] and the halogenating agent andthe subsequent reaction with the compound [39] are carried out under thesame reaction conditions as employed in the reaction between the abovecompound [37] or [34] and the halogenating agent and the subsequentreaction with the compound [39].

The desulfurization of the compound [47] to prepare the compound [48] iscarried out under the same reaction conditions as employed in thedesulfurization of the compound [40] or [44].

The reaction of converting the compound [48] into the compound [49] iscarried out by treating the former compound under the same reactionconditions as employed in the reaction of converting the compound [34]or [45] into the diazonium salt to prepare diazonium salt, which is thenreacted with MCN (wherein M is alkali metals such as sodium, potassium,etc. and metals such as silver, calcium, copper, etc.) in the presenceof a copper compound such as copper powder or copper sulfate. Thereaction is usually carried out at a temperature of from around 0° C. toaround 100° C., preferably from around 0° C. to around 70° C. for about0.5 to about 5 hours. The MCN is usually used in an amount of at least 1mole, preferably 1 to 10 moles per 1 mole of the compound [48].

The hydrolysis of the compound [49] can be carried out in the presenceof a suitable hydrolysis catalyst, including inorganic acids such ashydrohalogenic acids (e.g. hydrochloric acid, hydrobromic acid, etc.),mineral acids (e.g. sulfuric acid, phosphoric acid, etc.), and inorganicalkaline compounds such as alkali metal hydroxides (e.g. sodiumhydroxide, potassium hydroxide, etc.), alkali metal carbonates orbicarbonates (e.g. sodium carbonate, potassium carbonate, sodiumhydrogen carbonate, etc.), in the presence or absence of a solvent (e.g.water, or a mixture of water and a lower alcohol such as methanol,ethanol, etc.). The reaction is usually carried out at a temperature offrom 50° C. to 200° C., preferably from 70° C. to 180° C. for about 1 to10 hours. ##STR33## wherein R^(2'), X, X⁷, and R²⁹ are as defined aboveand X⁸ is a halogen atom.

The reaction of converting the compound [37⃡ into the compound [50] canbe carried out under the same reaction conditions as employed in theabove reaction of converting the compound [28] into the compound [29].

The nitration of the compound [37], [50] or [55] can be carried outunder the same reaction conditions as employed in the above nitration ofthe compound [28] or [29].

The hydrolysis of the compound [51] can be carried out under the samereaction conditions as employed in the above hydrolysis of the compound[1a].

The deamination of the compound [52] to prepare the compound [53] can becarried out under the same reaction conditions as employed in the abovedeamination of the compound [41].

The reduction of the compound [53] can be carried out in the samereaction conditions as employed in the above reduction of the compound[33] or [36].

The reaction of converting the compound [54] into the compound [55] canbe carried out in the same manner as in the above reaction of convertingthe compound [34] or [45] into the compound [35] or [42].

The compounds [3], [5], [7], [9], [1a], [1a'], [1b'], [23], [25] and[26], wherein R² is a saturated or unsaturated 5- to 9-memberedheterocyclic ring having a substituent of oxo, can be reduced to thecorresponding compounds, wherein R² is a saturated or unsaturated 5- to9-membered heterocyclic ring having a substituent of hydroxy. Thereduction can be carried out with a hydrogenating reducing agent in thepresence of a suitable solvent. The reducing agent includes, forexample, sodium borohydride, lithium aluminum hydride, diborane and thelike. The reducing agent is usually used in an amount of at least 1mole, preferably 1 to 5 moles per 1 mole of the starting material to bereduced. The solvent includes, for example, water, a (lower) alcoholsuch as methanol, ethanol or isopropanol, an ether such astetrahydrofuran, diethyl ether or diglyme, and the like. The reaction isusually carried out at a temperature of from around -60° C. to 50° C.,preferably from around -30° C. to room temperature for about 10 minutesto about 5 hours. In case of using lithium aluminum hydride or diboraneas the reducing agent, non-aqueous solvent is preferably employed suchas diethyl ether, tetrahydrofuran or diglyme.

In case of using sodium borohydride as the reducing agent, an inorganicbase such as sodium hydroxide can also be added to the reaction system.

The compounds wherein R² is a saturated or unsaturated 5- to 9-memberedheterocyclic ring having a substituent selected from the groupconsisting of a (lower) alkyl having at least 1 of a (lower)alkanoylamino and a (lower) alkoxycarbonylamino, a (lower) alkanoylaminoand a (lower) alkoxycarbonylamino can be hydrolized into thecorresponding compounds wherein R² is a saturated or unsaturated 5- to9-membered heterocyclic ring having a subsitituent selected from thegroup consisting of a (lower) alkyl having at least one amino and amino.The hydrolysis can be carried out under the same reaction conditions asemployed in the hydrolysis of the compound [1a] in the above reactionscheme-I.

The compounds wherein R² is a saturated or unsaturated 5- to 9-memberedheterocyclic ring having at least one --NH-- in the ring can beconverted into the compounds wherein R² is a saturated or unsaturated 5-to 9-membered heterocyclic ring substituted by at least one (lower)alkanoyl, by reacting the former compounds under the same reactionconditions as employed in the reaction of converting the compound [28]into the compound [29] in the above reaction scheme-IX.

The compounds [3], [5], [7], [9], [1a], [1a'], [1b], [1b'], [23], [25]and [26] wherein R¹ is a phenyl having at least one (lower) alkoxy onthe phenyl ring can be converted into the corresponding compoundswherein R¹ is a phenyl having at least one hydroxy on the phenyl ring,by heating the former compounds in an aqueous hydrobromic acid solution.

The compound [1] wherein R³ is a halogen atom can be converted into thecorresponding compound [1] wherein R³ is hydroxy, by treating the formercompound in water and a basic compound such as sodium hydroxide,potassium hydroxide or barium hydroxide at from room temperature toaround 200° C., preferably from room temperature to around 150° C. forabout 1 to 15 hours. ##STR34## wherein R^(2'), R³ and X are as definedabove, and R^(6a) is hydrogen tom or a (lower) alkyl, R^(1a) is a(lower) alkyl having 1 to 3 of hydroxy, R^(1b) is a (lower) alkyl having1 to 3 of a (lower) alkanoyloxy, R^(1c) is a (lower) alkyl having 1 to 3of halogen atoms and R^(1d) is a (lower) alkenyl.

The reaction of converting the compound [1k] into the compound [1l] canbe carried out under the same reaction conditions as employed in theabove reaction of converting the compound [28] into the compound [29].

The hydrolysis of the compound [1l] can be carried out under the samereaction conditions as employed in the above hydrolysis of the compound[1a].

The halogenation of the compound [1k] can be carried out under the samereaction conditions as employed in the above halogenation of thecompound [2].

The reaction of converting the compound [1k] into the compound [1n] iscarried out in a suitable solvent or without a solvent in the presenceof a hydrohalogenic acid such as hydochloric acid or hydrobromic acid,an inorganic acid such as sulfuric acid, boric acid or potassiumhydrogensulfate, or an organic acid such as oxalic acid. The solventemployed in the reaction includes, for example, water, an ether such asdioxane, tetrahydrofuran or diethyl ether, a halogenated hydrocarbonsuch as dichloromethane, chloroform or carbon tetrachloride, an aromatichydrocarbon such as benzene, toluene or xylene, or a mixture thereof.The reaction is usually carried out at a temperature of from around 50°C. to around 350° C., preferably from around 80° C. to around 300° C.for about 10 minutes to about 10 hours.

The reaction of converting the compound [1l] into the compound [1n] iscarried out in a suitable solvent or without a solvent. The solventemployed in the reaction may be any which is exemplified in the abovereaction of converting the compound [1k] into the compound [1n]. Thereaction is usually carried out at a temperature of from roomtemperature to around 150° C., preferably from room temperature toaround 100° C. for about 10 minutes to about 10 hours. The reaction mayalso be conducted in the presence of an inorganic base such as sodiumcarbonate, potassium carbonate, sodium hydrogen carbonate, potassiumhydrogen carbonate, sodium hydroxide, potassium hydroxide, lithium saltsuch as lithium chloride or lithium carbonate, or an organic base suchas DBU, pyridine, triethanol amine or triethyl amine.

The reaction of converting the compound [1m] into the compound [1n] iscarried out in a suitable solvent in the presence of a basic compound.The solvent and the basic compound employed in the reaction may be anywhich is exemplified in the above reaction of converting the compound[1l] into the compound [1n]. The reaction is usually carried out at atemperature of from room temperature to around 200° C., preferably fromroom temperature to around 150° C. for about 1 to about 10 hours.

The compounds [1k], [1l], [1m] and [1n] wherein R⁶ a is a (lower) alkylcan be converted into the corresponding compounds wherein R^(6a) ishydrogen atom, by hydrolyzing the former compounds under the samereaction conditions as employed in the above hydrolysis of the compound[1a].

In the hydrolysis of the compound [1±] wherein R^(6a) is a (lower)alkyl, R^(6a) is also hydrolyzed in some cases to give the compound [1l]wherein R^(6a) is hydrogen atom, which can easily be separated from thereaction mixture.

In the halogenation of the compound [1k] wherein R⁶ a is hydrogen atom,the carboxy in the compound is also halogenated in some cases but thisone can be easily separated from the reaction mixture. ##STR35## WhereinX², X³ and X⁴ are as defined above, R³² and R³³ each are a (lower)alkyl.

The esterification of the compound [56] is carried out in a (lower)alcohol such as methanol, ethanol or isopropanol in the presence of ahalogenating agent such as an acid such as hydrochloric acid or sulfuricacid, thionyl chloride, phosphorus oxychloride, phosphorus pentachlorideor phosphorus trichloride. The reaction is usually carried out at atemperature of from around 0° C. to 150° C., preferably from around 50°C. to around 100° C. for about 1 to 10 hours.

The reduction of the compound [57] can be carried out under the samereaction conditions as employed in the above reduction of the compound[33] or [36].

The halogenation of the compound [58] is carried out in a suitablesolvent in the presence of a halogenating agent. The halogenating agentemployed in the reaction includes a halogen such as bromine or chlorine,iodine chloride, sulufuryl chloride, N-halogenosuccinimide such asN-bromosuccinimide or N-chlorosuccinimide. The halogenating agent isusually used in an amount of from 1 to 10 moles, preferably from 1 to 5moles per 1 mole of the compound [58]. The solvent includes ahalogenated hydrocarbon such as dichloromethane, dichloroethane,chloroform or carbon tetrachloride, a (lower) alkanoic acid such asacetic acid or propionic acid, water and the like. The reaction isusually carried out at a temperature of from around 0° C. to around theboiling point of the solvent, preferably from around 0° C. to around 40°C. for about 0.1 to about 10 hours.

The reaction of converting the compound [59] into the compound [60] canbe carried out under the same reaction conditions as employed in theabove reaction of converting the compound [34] or [45] into the compound[35] or [42].

The hydrolysis of the compound [60] can be carried out under the samereaction conditions as employed in the above hydrolysis of the compound[1a].

The compounds [1a] in the reaction scheme-I and the compounds [1b] and[1b'] in the reaction scheme-II are useful not only as an intermediatefor preparing the compound [1] of the present invention withantimicrobial activities, but also as an antimicrobial agent becausethey also have antimicrobial activities.

The compound [1] of the present invention can easily be converted into asalt thereof by treating with a pharmaceutically acceptable acid orbase. The acid includes inorganic acids such as hydrochloric acid,sulfuric acid, phosphoric acid and hydrobromic acid and organic acidssuch as oxalic acid, maleic acid, fumaric acid, malic acid, tartaricacid, citric acid, benzoic acid, lactic acid, methanesulfonic acid andpropionic acid. The base includes sodium hydroxide, potassium hydroxide,calcium hydroxide, sodium carbonate, potassium hydrogen carbonate, andthe like.

The compound thus obtained can easily be isolated and purified byconventional methods, such as, for example, extraction with solvents,dilution method, recrystallization, column chromatography andpreparative thin layer chromatography.

The compound [1] of the present invention or salts thereof show anexcellent antimicrobial activity against mycoplasma, Pseudomonasaeruginosa, anaerobic bacteria, resistant cells against variousantimicrobials, clinically isolated bacteria, and gram negative and grampositive bacteria such as Enterococcus faecalis and Staphylococcuspyogenes and hence are useful as an antimicrobial agent for thetreatment of diseases induced by these microorganisms. These compoundsalso show low toxicity and less side effect and are characteristic ingood absorbability and in sustained activity. Moreover, the compoundsare highly excreted via urine and hence are useful for the treatment ofurinary infectious diseases, and further because of easy excretion viabile, they are also useful for the treatment of intestinal infectiousdiseases.

Among the compounds [1] of the present invention, the preferable onesare the compounds wherein R¹ is unsubstituted cyclopropyl, X is chlorineor fluorine atom, most preferably fluorine atom, R⁴ is a (lower) alkylsuch as, preferably methyl or ethyl, most preferably methyl.

The absorbability of the compounds of the present invention in theliving body can be increased by converting them into the correspondingsalt such as, for example, lactate or hydrochloride.

The compounds of the present invention are usually used in the form of ausual pharmaceutical preparation. The pharmaceutical preparation can beprepared in admixture with conventional pharmaceutically acceptablediluents or carriers, such as fillers, bulking agents, binding agents,wetting agents, disintegrators, surfactants and lubricating agents. Thepharmaceutical preparation includes various preparations suitable fortreatment of the diseases, for example, tablets, pills, powders,solutions, suspensions, emulsions, granules, capsules, suppositories,injections such as solutions and suspensions, and the like. In thepreparation of tablets, there may be used any conventional carriers, forexample, excepients such as lactose, white sugar, sodium chloride,glucose, urea, starches, calcium carbonate, kaolin, crystallinecellulose and silicate, binding agents such as water, ethanol, propanol,simple syrup, glucose solution, starch solution, gelatin solution,carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphateand polyvinylpyrrolidone, disintegrators such as dry starch, sodiumalginate, agar powder, laminaran powder, sodium hydrogen carbonate,calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodiumlaurylsulfate, stearic monoglyceride, starches and lactose,disintegration inhibitors such as white sugar, stearin, cacao butter andhydrogenated oils, absorption promoters such as quaternary ammoniumsalts and sodium laurylsulfate, wetting agents such as glycerin andstarches, adsorbents such as starches, lactose, kaolin, bentonite andcolloidal silicates, rublicants such as purified talc, stearates, boricacid powder and polyethylene glycol, and the like. The tablets may alsobe coated with conventional coating agents, for example, may be in theform of a sugar coated tablet, a gelatin-coated tablets, an entericcoating tablet, a film coating tablet, or a double or multiple layerstablet. In the preparation of pills, there may be used conventionalcarries, including excipients such as glucose, lactose, starches, cacaobutter, hydrogenated vegetable oils, kaolin and talc, binding agentssuch as gum arabic powder, tragacanth powder, gelatin and ethanol,disintegrators such as laminaran and agar, and the like. In thepreparation of suppositories, there may be used conventional carriers,such as, for example, polyethylene glycol, cacao butter, higheralcohols, higher alcohol esters, gelatin and semi-synthetizedglycerides. In the preparation of injections, the solutions, emulsionsor suspensions of the compounds are sterilized and are preferably madeisotonic with the body liquid. These solutions, emulsions andsuspensions are prepared by admixing the active compound with aconventional diluent, such as water, aqueous lactic acid solution, ethylalcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylatedisostearyl alcohol or polyoxyethylene sorbitan fatty acid esters. Thepreparations may also be incorporated with sodium chloride, glucose orglycerin in an amount sufficient to make them isotonic with the bodyliquid. The preparations may also be incorported with conventionalsolubilizers, buffering agents, anesthetizing agents, and further, withcoloring agents, preservatives, perfumes, flavors, sweetening agents,and other medicaments. The preparations in the form of a paste, cream orgel may be prepared by using as a diluent white vaseline, paraffin,glycerin, cellulose derivatives, polyethylene glycol, silicone,bentonite, or the like. When the compound of the active ingredientprecipitates in the injection, an acid such as, for example,methanesulfonic acid, propionic acid, hydrochloric acid, succinic acidor lactic acid may be added to the injection as required to preserve theinjection in a stable solution

The pharmaceutical preparation of the present invention may also be inthe form of an infusable or injectable solution containing the abovecompound [1] or a salt thereof such as lactate and an acid not producinga precipitate. The acid not producing a precipitate includes, forexample, lactic acid, methanesulfonic acid, propionic acid, hydrochloricacid, succinic acid, and the like, preferably lactic acid. In case ofusing lactic acid, the acid is usually used in an amount of from around0.1 to around 10% by weight, preferably from around 0.5 to around 2% byweight, based on the weight of the above infusable or injectablesolution. In case of using an acid other than lactic acid, the acid isusually used in an amount of from around 0.05 to around 4% by weight,preferably from around 0.3 to around 2% by weight, based on the weightof the above solution. The above infusable or injectable solution mayoptionally be added with conventional additives, which includes, forexample, a thickener, an absorption promoter or inhibitor, acrystallization inhibitor, a complex-forming agent, an antioxidant, anisotonicity-giving agent, or a hydrating agent, and the like. The pH ofthe solution can properly be adjusted by adding an alkali such as sodiumhydroxide, and is usually adjusted within the range of from 2.5 to 7.The infusable or injectable solution thus prepared has an excellentstability, and can be stored and preserved for a long time withretaining the solution state.

The active compounds [1] or salts thereof may be contained in any amountin the preparations, and are usually contained in an amount of from 1 to70 % by weight based on the whole weight of the preparations.

The pharmaceutical preparations of the present invention can beadministered in any methods. Suitable method for administration may beselected in accordance with the preparation form, age and sex ofpatients, severity of the diseases, and the like. For instance, tablets,pills, solutions, suspensions, emulsions, granules and capsules areadministered in oral route. In case of injection, it is administeredintravenously in a single form or together with an auxiliary liquid suchas glucose or amino acid solution. The injections may also beadministered in intramuscular, intracutaneous, subcutaneous, orintraperitoneal route. Suppositories are administered in intrarectalroute.

The dosage of the pharmaceutical preparations of the present inventionmay vary according to administration methods, age and sex of patients,severity of the diseases, and the like, usually in the range of about0.2 to about 100 mg of the active compound [1]or a salt thereof per 1 kgbody weight of the patient per day. The preparation is usuallyadministered by dividing into 2 to 4 times per day.

The present invention is illustrated by the following ReferenceExamples, Examples, Experiments and Preparations. It is to be understoodthat the present invention is not limited to these Examples orExperiments and various changes and modifications can be made withoutdeparting from the scope and spirit of the present invention.

Reference Example 1

To 2,4,5-trifluoroaniline (35.0 g) are added anhydrous dichloromethane(530 ml) and dimethyl sulfide (24.6 ml) and the mixture is cooled to 0°C. Thereto N-chlorosuccinimide (38.2 g) is gradually added below 5° C.After the mixture is stirred at the same temperature for 15 minutes,triethylamine (47.7 ml) is gradually added. After reflux for 12 hours,the resultant is made alkaline with 5 % aqueous sodium hydroxidesolution, extracted with dichloromethane, and the extract is dried oversodium sulfate and concentrated. The residue is purified with columnchlomatography (silica-gel, dichloromethane: n-hexane=1:4) to give2-methylthiomethyl-3,4,6-trifluoroaniline (22.3 g).

¹ H-NMR (CDCl₃) δppm: 2.03 (3H, s), 3.76 (2H, d, J=1.5 Hz), 4.03 (2H,brs), 6.48 (1H, dt, J=7.2 Hz, 10.1 Hz)

Reference Example 2

To 2-methylthiomethyl-3,4,6-trifluoroaniline (22.2 g) are added ethanol(400 ml) and Raney nickel (200 g) and the mixture is stirred at roomtemperature for 30 minutes. After the catalyst is filtered off, thefiltrate is added with water and extracted with dichloromethane. The isdried over magnesium sulfate and concentrated to give2-methyl-3,4,6-trifluoroaniline (12.3 g).

¹ H-NMR (CDCl₃) δppm: 2.13 (3H, d, J=2.1 Hz), 3.56 (2H, brs), 6.75 (1H,dt, J=7.2 Hz, 10.2 Hz)

Reference Example 3

To 2-methyl-3,4,6-trifluoroaniline (10.6 g) is added a mixture of conc.sulfuric acid (13.8 ml) and water (46 ml) and the mixture is cooled.Thereto an aqueous solution (20 ml) of sodium nitrite (5.5 g) is addeddropwise at 0°-5° C. The solution is gradually added to a mixture ofcopper (II) sulfate 5 hydrate (41 g), potassium cyanide (43 g), ammoniumhydroxide (60 ml) and water (260 ml) at 10°-30° C. The mixture isextracted with dichloromethane and the extract is dried over sodiumsulfate, concentrated and the residue is purified with columnchromatography (silica-gel, dichloromethane : n-hexane =1 : 4) to give2-methyl-3,4,6-trifluorobenzonitrile (4.3 g).

¹ H-NMR (CDCl₃) δppm: 2.52 (3H, d, J=2.5 Hz), 6.94 (1H, dt, J=6.2 Hz,8.9 Hz)

Reference Example 4

To 2-methyl-3,4,6-trifluorobenzonitrile (4.3 g) is added 50 % sulfuricacid (40 ml) and the mixture is heated at 150°-160° C. for 6 hours.After cooling, the mixture is poured into ice-water and extracted withdiethyl ether. The ether layer is added with water and made alkalinewith 5 % aqueous sodium hydroxide solution while the water layer is madeacidic with conc. hydrochloric acid. The resultant is subjected toextraction with diethyl ether, and the extract is dried over magnesiumsulfate and concentrated to give 2-methyl-3,4,6-trifluorobenzoic acid(3.3 g).

¹ H-NMR (CDCl₃) δppm: 2.47 (3H, d, J=2.6 Hz), 6.88 (1H, dt, J=6.3 Hz,9.5 Hz)

Reference Example 5

To 2-methyl-3,4,6-trifluorobenzoic acid (3.2 g) is added thiony chloride(7 ml) and the mixture is refluxed for hour. After concentrating,2-methyl-3,4,6-trifluorobenzoyl chloride (3.3 g) is obtained.

Separately, two drops of carbon tetrachloride are added to a solution ofmetallic magnesium (0.4 g) in absolute ethanol (0.9 ml). When thereaction starts, a mixture of diethyl malonate (2.6 ml), absoluteethanol (1.6 ml) and anhydrous toluene (6 ml) is added dropwise below60° C. After stirring at 60° C. for 1 hour, the reaction mixture iscooled to 0° C. and thereto a solution of2-methyl-3,4,6-trifluorobenzoyl chloride prepared above in toluene (5ml) is added dropwise. After stirring for 30 minutes, a mixture of conc.sulfuric acid (0.4 ml) and water (6 ml) is added and the mixture isextracted with diethyl ether, and the extract is dried over magnesiumsulfate and concentrated to give diethyl2-methyl-3,4,6-trifluorobenzoylmalonate (5.2 g).

Reference Example 6

To diethyl 2-methyl-3,4,6-trifluorobenzoylmalonate (5.1 g) are addedwater (20 ml) and p-toluenesulfonic acid (30 mg) and the mixture isrefluxed for 2.5 hours. After cooling, the resultant is extracted withdiethyl ether, and the extract is dried over magnesium sulfate andconcentrated to give ethyl 2-methyl-3,4,6-trifluorobenzoylacetate (3.3g).

Reference Example 7

To ethyl 2-methyl-3,4,6-trifluorobenzoylacetate (3.2 g) are added aceticanhydride (3.0 g) and triethoxymethane (2.7 g) and the mixture isrefluxed for 1 hour. After concentrating, ethyl2-(2-methyl-3,4,6-trifluorobenzoyl)-3-ethoxyacrylate (3.5 g) isobtained.

Reference Example 8

Ethyl 2-(2-methyl-3,4,6-trifluorobenzoyl)-3-ethoxyacrylate (3.5 g) isdissolved in ethanol (25 ml) and thereto cyclopropylamine (0.84 ml) isadded dropwise under ice-cooling. After stirring at room temperature for30 minutes, the mixture is concentrated and the residue is purified withcolumn chromatography (silica-gel, dichloromethane: n-hexane =1 : 1) togive ethyl2-(2-methyl-3,4,6-trifluorobenzoyl)-3-cyclopropylaminoacrylate (2.7 g).

Reference Example 9

Ethyl 2-(2-methyl-3,4,6-trifluorobenzoyl)-3-cyclopropylaminoacrylate(2.6 g) is dissolved in anhydrous dioxane (26 ml) and thereto 60 %sodium hydride (0.38 g) is gradually added under ice-cooling. Afterstirring at room temperature for 30 minutes, the reaction mixture ispoured into ice-water and extracted with dichloromethane. The extract isdried over magnesium sulfate and concentrated. The residue is added withdiethyl ether and crystals are filtered, which are recrystallized fromethanol to give ethyl1-cyclopropyl-6,7-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate(2.0 g), m.p. 185°-187° C.

Reference Example 10

To ethyl1-cyclopropyl-6,7-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate(1.9 g) are added 90 % acetic acid (20 ml) and conc. hydrochloric acid(5 ml) and the mixture is refluxed for 2 hours. After cooling, theprecipitated crystals are isolated, washed with water, ethanol, anddiethyl ether in this order to give1-cyclopropyl-6,7-difluoro-5-methyl-1,4,-dihydro-4-oxoquinoline-3-carboxylicacid (1.6 g), as colorless needles, m.p. 294°-298° C.

¹ H-NMR (CF₃ COOD) δppm: 1.43-1.55 (2H, m), 1.65-1.81 (2H, m), 3.06 (3H,d, J=2.8 Hz), 4.08-4.20 (1H, m), 8.40 (1H, dd, J=6.8 Hz, 10.3 Hz), 9.46(1H,s)

Reference Examples 11

Employing ethyl 2-(2-methyl-3,4,6-trifluorobenzoyl)-3-ethoxyacrylate(1.0 g) and p-fluoroaniline (0.39 g), the procedure of Reference Example8 is repeated to give ethyl2-(2-methyl-3,4,6-trifluorobenzoyl)-3-(4-fluorophenyl)aminoacrylate,which is then treated with 60 % sodium hydride (0.15 g) as in ReferenceExample 9 to give ethyl1-(4-fluorophenyl)-5-methyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(0.64 g), as white crystals (recrystallized from ethanol), m.p.256°-259° C.

Reference Examples 12

Employing ethyl1-(4-fluorophenyl)-5-methyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(0.56 g), conc. hydrochloric acid (1.5 ml), and 90 % acetic acid (6 ml),the procedure of Reference Example 10 is repeated to give1-(4-fluorophenyl)-5-methyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (0.49 g), as white crystals, m.p. 255°-257° C.

Reference Examples 13

Employing ethyl 2-(2-methyl-3,4,6-trifluorobenzoyl)-3-ethoxyacrylate(1.0 g) and 70 % aqueous ethylamine solution (0.24 ml), the procedure ofReference Example 8 is repeated to give ethyl2-(2-methyl-3,4,6-trifluorobenzoyl)-3-ethylaminoacrylate, which is thentreated with 60 sodium hydride (0.15 g) as in Reference Example 9 togive ethyl1-ethyl-5-methyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(0.6 g), as white crystals, m.p. 157°-159° C.

Reference Example 14

Employing ethyl1-ethyl-5-methyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(0.55 g), conc. hydrochloric acid (1.5 ml) and 90 % acetic acid (6 ml),the procedure of Reference Example 10 is repeated to give1-ethyl-5-methyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (0.40 g), as white crystals, m.p. >300° C.

¹ H-NMR (DMSO-d₆) δppm: 1.37 (3H, t, J=7.2 Hz), 2.82 (3H, d, J=3.2 Hz),4.54 (2H, q, J=7.2 Hz), 8.07 (¹ H, dd, J=7.2 Hz, 9.8 Hz), 9.00 (¹ H, s),15.25 (¹ H, s)

Reference Example 15

To 2-methyl-3-nitrobenzoic acid (10.0 g) is added methanol (100 ml) andthereto thionyl chloride (8 ml) is added dropwise at room temperature.After reflux for 2 hours, the reaction mixture is poured into ice-waterand extracted with dichloromethane. The solvent is concentrated to givemethyl 2-methyl-3-nitrobenzoate (10.8 g).

(¹ H NMR (CDCl₃) δ: 2.63 (3H, s), 3.94 (3H, s), 7.38 (1H, t, J=8 Hz),7.84 (1H, d, J=8 Hz), 7.99 (1H, d, J=8 Hz)

Reference Example 16

Methyl 2-methyl-3-nitrobenzoate (10.0 g) is dissolved in acetic acid (50ml) and thereto 5% Pd-C (1 g) is added to carry out catalytic reductionat room temperature under 1 atm. After 1.5 hours, the catalyst isfiltered off. The reaction mixture is concentrated, and thereto is addedwater, and the mixture is made alkaline with potassium carbonate,followed by extraction with dichloromethane. The solvent is concentratedto give methyl 2-methyl-3-aminobenzoate (8.6 g).

¹ H-NMR (CDCl₃) δppm: 2.34 (3H, s), 3.55-3.85 (2H, brs), 3.87 (3H, s),6.80 (1H, d, J=8 Hz), 7.04 (1H, t, J=8 Hz), 7.20 (1H, d, J=8 Hz)

Reference Example 17

To methyl 2-methyl-3-aminobenzoate (1.6 g) are added acetic acid (20 ml)and sodium acetate (1.6 g). Thereto a solution of bromine (3.1 g) inacetic acid (5 ml) is added dropwise below 20° C. over a period of 10minutes. After the mixture is stirred at room temperature for 30minutes, the reaction mixture is poured into ice-water and the resultantis extracted with diethyl ether The ether layer is neutralized withpotassium carbonate and dried. The solvent is concentrated to givemethyl 2-methyl-3-amino-4,6-dibromobenzoate (2.8 g).

¹ H NMR (CDCl₃) δ: 2.14 (3H, s), 3.93 (3H, s), 4.05-4.30 (2H, brs), 7.52(1H, s)

Reference Example 18

To methyl 2-methyl-3-amino-4,6-dibromobenzoate (1.4 g) are added ethanol(5 ml) and 42% tetrafluoroboric acid (2.5 ml), and thereto is addeddropwise a solution of sodium nitrite (0.33 g) in water (1 ml) below 5°C. After stirring the mixture for 10 minutes, the precipitated crystalsare filtered and washed with a small amount of water, ethanol anddiethyl ether in this order to give methyl2-methyl-4,6-dibromo-3-benzoate diazonium tetrafluoroborate (1.6 g),m.p. 202°-204° C. (dec.).

Reference Example 19

Methyl 2-methyl-4,6-dibromo-3-benzoate diazonium tetrafluoroborate (1.3g) is heated at 200° C. for 10 minutes. After cooling, the reactionmixture is added with ice-water and extracted with dichloromethane. Thesolvent is concentrated and the obtained residue is purified bysilica-gel column-chromatography (eluent; chloroform: n-hexane=1:4) togive methyl 2-methyl-3-fluoro-4,6-dibromobenzoate (0.6 g).

¹ H NMR (CDCl₃) δ: 2.27 (3H, d, J=2.5 Hz), 3.95 (3H, s), 7.63 (1H, d,J=5.8 Hz)

Reference Example 20

To methyl 2-methyl-3-fluoro-4,6-dibromobenzoate (75.5 g) are addedethanol (460 ml) and 10% aqueous solution of sodium hydroxide (460 ml)and the mixture is refluxed for 2 hours. After cooling, the reactionmixture is diluted with water and extracted with diethyl ether. Theaqueous layer is made acidic with conc. hydrochloric acid and extractedwith diethyl ether The solvent is concentrated to give2-methyl-3-fluoro-4,6-dibromobenzoic acid (61 g), m.p. 144°-146° C.

Reference Example 21

Employing 4,6-dibromo-3-fluoro-2-methylbenzoic acid (2.0 g), theprocedure of Reference Example 5 is repeated to give4,6-dibromo-3-fluoro-2-methylbenzoyl chloride (2.0 g).

¹ H-NMR (CDCl₃) δppm: 2.37 (3H, d, J=2.5 Hz), 7.69 (1H, d, J=5.8 Hz)

Reference Example 22

Employing diethyl 4,6-dibromo-3-fluoro-2-methylbenzoyl chloride (2.0 g),the procedure of Reference Example 5 is repeated to give diethyl4,6-dibromo-3-fluoro-2-methylbenzoylmalonate (2.6 g).

Reference Example 23

Employing diethyl 4,6-dibromo-3-fluoro-2-methylbenzoylmalonate (2.6 g),the procedure of Reference Example 6 is repeated to give ethyl4,6-dibromo-3-fluoro-2-methylbenzoylacetate (2.1 g).

Reference Example 24

Employing ethyl 4,6-dibromo-3-fluoro-2-methylbenzoylacetate (2.1 g), theprocedure of Reference Example 7 is repeated to give ethyl2-(4,6-dibromo-3-fluoro-2-methylbenzoyl)-3-ethoxyacrylate (2.1 g).

Reference Example 25

Employing ethyl2-(4,6-dibromo-3-fluoro-2-methylbenzoyl)-3-ethoxyacrylate (69.5 g), theprocedure of Reference Example 8 is repeated to give ethyl2-(4,6-dibromo-3-fluoro-2-methylbenzoyl)-3-cyclopropylaminoacrylate(48.1 g).

Reference Example 26

A mixture comprising ethyl2-(4,6-dibromo-3-fluoro-2-methylbenzoyl)-3-cyclopropylaminoacrylate(45.0 g), potassium carbonate (16.7 g) and dimethylformamide (450 ml) isreacted at 140° C. for 30 minutes. After cooling, the reaction mixtureis poured into ice-water and the precipitated crystals are filtered,which are recrystallized from ethanol to give ethyl1-cyclopropyl-6-fluoro-7-bromo-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate(33.6 g), as white crystals, m.p. 195°-197° C.

Reference Example 27

Employing ethyl1-cyclopropyl-6-fluoro-7-bromo-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate(32.5 g), the procedure of Reference Example 10 is repeated to give1-cyclopropyl-6-fluoro-7-bromo-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (27.2 g), as white crystals, m.p. 237°-239° C.

Reference Example 28

To1-cyclopropyl-6-fluoro-7-bromo-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (0.2 g) is added thionyl chloride (2 ml) and the mixture isrefluxed for 1 hour. After cooling, the reaction mixture is poured intoice-water and made alkaline with 10% aqueous sodium hydroxide solution.After stirring for 30 minutes, the resultant is extracted withdichloromethane. The aqueous layer is made acidic with 10% hydrochloricacid and then extracted with dichloroethane. The solvent is concentratedand the residue is recrystallized from acetic acid to give1-cyclopropyl-6-fluoro-7-chloro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (80 mg), as white crystals, m.p. 258°-260° C.

Reference Example 29

Employing ethyl 2-(2-methyl-3,4,6-trifluorobenzoyl)-3-ethoxyacrylate(1.0 g) and 2,4-difluoroaniline (0.5 g), the procedure of ReferenceExample 8 is repeated to give ethyl2-(2-methyl-3,4,6-trifluorobenzoyl)-3-(2,4difluorophenyl)aminoacrylate(1.1 g).

¹ H-NMR (CDCl₃) δppm: 0.95 (3H, t, J=7.2 Hz), 2.23 (3H, d, J=2.4 Hz),4.06 (2H, q, J=7.2 Hz), 6.70-6.83 (1H, m), 6.91-7.03 (2H, m), 7.26-7.45(1H, m), 8.60 (1H, d, J=13.8 Hz), 11.36 (1H, d, J=13.8 Hz)

Reference Example 30

Employing ethyl2(2-methyl-3,4,6-trifluorobenzoyl)-3-(2,4-difluorophenyl)aminoacrylate(1.1 g) and 60 sodium hydride (0.13 g), the procedure of ReferenceExample 9 is repeated to give ethyl1-(2,4-difluorophenyl)-5-methyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(0.7 g).

¹ H-NMR (CDCl₃) δppm: 1.38 (3H, t, J=7.1 Hz), 2.91 (3H, d, J=3 Hz), 4.38(2H, q, J=7.1 Hz), 6.46 (1H, dd, J=6.9 Hz, 11.1 Hz), 7.10-7.26 (2H, m),7.38-7.56 (1H, m), 8.26 (1H, s)

Reference Example 31

Employing ethyl1-(2,4-difluorophenyl)-5-methyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(0.7 g), the procedure of Reference Example 10 is repeated to give1-(2,4-difluorophenyl)-5-methyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (0.5 g), colorless needles (recrystallized from acetic acid), m.p.280°-281° C.

Example 1

To 3-(1-piperazinyl)-4-fluoro-5-methyl-6-nitro-N-cyclopropylaniline(1.57 g) is added diethyl ethoxymethylenemalonate (1.45 ml) and themixture is heated at 150° C. for 25 hours. After cooling, the reactionproduct is purified by silica-gel column-chromatography (dichloromethane: methanol=100:1) to give diethyl[N-cyclopropyl-N-[3-(1-piperazinyl)-4-fluoro-5-methyl-6-nitrophenyl]aminomethylene]malonate(1.50 g). The product is dissolved in acetic anhydride (7.9 ml) andthereto conc. sulfuric acid (3.16 ml) is added dropwise at 50°-60° C.,followed by stirring for 30 minutes. The resultant mixture is pouredinto ice-water, neutralized, extracted with dichloromethane and theextract is dried The solvent is distilled off under reduced pressure.Purification by silica-gel column-chromatography (dichloromethane:methanol=10:1) to give ethyl7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate(26 mg).

Example 2

To ethyl7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate(23 mg) are added 10% aqueous solution of sodium hydroxide (3 ml) andethanol (3 ml), and the mixture is refluxed for 1 hour. After cooling,the reaction mixture is diluted with water and washed withdichloromethane. The aqueous layer is made acidic with acetic acid andthen made weakly alkaline with an aqueous sodium hydrogen carbonate. Theresultant product is extracted with dichloromethane and the extract isdried. The solvent is distilled off under reduced pressure and to theresidue is added ethanol. The precipitated crystals are filtered andrecrystallized from dimethylformamide to give7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,,4-dihydro-4-oxoquinoline-3-carboxylicacid (12 mg), as white powder, m.p. 231°-233° C.

Example 3

To6,7-difluoro-1-cyclopropyl-5-methyl-1,4-difluoro-4-oxoquinoline-3-carboxylicacid - B(OCOCH₃)₂ chelate (1.20 g) are added anhydrous 1-piperazine(0.86 g) and dimethylacetamide (6 ml), and the mixture is reacted at 50°C. for 20 hours. After concentrating, the obtained residue is dissolvedin acetone (20 ml) and thereto conc. hydrochloric acid (5 ml) is added,followed by stirring at room temperature for 30 minutes. The solvent isdistilled off and the resultant residue is treated with water andextracted with dichloromethane. The aqueous layer is neutralized with anaqueous sodium hydrogen carbonate and extracted with dichloromethane.After drying over magnesium sulfate, the residue is treated withethanol. The precipitated crystals are filtered and recrystallized fromdimethylformamide to give7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (96 mg), as white powder, m.p. 231°-233° C.

Example 4

To a suspension of6,7-difluoro-1-cyclopropyl-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (0.15 g) in dimethylformamide (3 ml) is added anhydrous1-piperazine (0.23 g) and the mixture is stirred at 90° C. for 30minutes. After the reaction is completed, the reaction mixture isconcentrated, and to the obtained residue is added ethanol Theprecipitated crystals are filtered and recrystallized fromdimethylformamide to give7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (0.1 g), as white powder, m.p. 231°-233° C.

Example 5

Starting from suitable materials, the procedure of the above Examples1-4 is repeated to give the following compounds.

1)7-(4-Methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, m.p. 229°-232° C., pale yellow prisms (recrystallized fromethanol)

2)7-(3-Methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, m.p. 206°-208° C., white powder (recrystallized from ethylacetate - ethanol)

3)7-(3-Amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, m.p. 267°-270° C., white powder (recrystallized fromdimethylformamide)

4)7-Morpholino-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, m.p. 245°-247° C., white powder (recrystallized from ethanol)

5)7-(3-Amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid hydrochloride (trans form), m.p. 272°-275° C. (dec.) white powder(recrystallized from methanol - ethyl acetate)

6)7-(3-Aminomethyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid hydrochloride, m.p. 280°-283° C. (dec.), white powder(recrystallized from methanol - water)

7)7-(4-Hydroxy-1-piperidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, m.p. 220°-221° C., colorless needles (recrystallized frommethanol)

8)7-(4-Fluoro-1-piperidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, m.p. 204°-207° C., white powder (recrystallized from ethanol)

9)7-[3-(N-t-Butoxycarbonyl-N-methylamino)-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, m.p. 210°-212° C., white powder (recrystallized from ethanol)

10)7-(3-t-Butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (cis form), m.p. 239°-241° C., white powder (recrystallized fromethanol)

11)7-[3-(N-t-Butoxycarbonyl-N-ethylaminomethyl)1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, m.p. 175°-177° C., white powder (recrystallized from ethanol)

12)7-(3-Amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid hydrochloride (cis form), m.p. 280°-284° C. (dec.), pale yellowpowder (recrystallized from ethanol)

13) 7-(3-Ethylaminomethyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride, m.p.236°-239° C., pale yellow powder (recrystallized from ethanol)

14)7-(1,4-Diazabicyclo[4,3,0]nonan-4-yl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, m.p. 203°-205° C., colorless needles (recrystallized from ethanol)

15)7-(4-Acetyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, m.p. 261°-263° C., white powder (recrystallized from ethanol)

16)7-(3-Methylamino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, m.p. 194°-197° C., white powder (recrystallized fromdimethylformamide)

17)7-(3-t-Butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (trans form), m.p. 226°-229° C., white powder (recrystallized fromethanol)

18)7-[4-(5-Methyl-2-oxo-1,3-dioxolen-4-yl)methyl-1-piperazinyl]-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid

¹ H-NMR (CDCl₃) δppm: 1.14-1.24 (2H, m), 1.26-1.41 (2H, m), 2.16 (3H,s), 2.72-2,84 (7H, m), 3.28-3.53 (7H, m), 7.29 (1H, d, 8.2 Hz), 8.73(1H, s), 15.57 (1H, s)

19)7-(1-Piperazinyl)-1-(4-fluorophenyl)-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, m.p. 278°-282° C. (dec ), yellowish crystals (recrystallized fromdimethylformamide)

20)7-(3-t-Butoxycarobonylamino-1-pyrrolidinyl)-1-(4-fluorophenyl)-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, m.p. 249°-250° C., white crystals (recrystallized from ethanol)

21)7-(3-Amino-1-pyrrolidinyl)-1-(4-fluorophenyl)-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid hydrochloride, m.p. 292°-295° C. (dec.), pale yellowish whitecrystals (recrystallized from methanol water)

22)7-(1-Piperazinyl)-1-ethyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, m.p. 225°-227° C., white crystals (recrystallized fromdimethylformamide)

23)7-(3-t-Butoxycarbonylamino-1-pyrrolidiny)-1-ethyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, m.p. 230°-231° C., white crystals (recrystallized from ethanol)

24)7-(3-Amino-1-pyrrolidinyl)-1-ethyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid hydrochloride, m.p. 275°-281° C. (dec.), yellowish crystals(recrystallized from ethanol)

25)7-(4-Methyl-1-piperazinyl)-1-(4-fluorophenyl)-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, m.p. 274°-276° C. (dec.), white crystals (recrystallized fromethanol)

26)7-(4-Methyl-1-piperazinyl)-1-(2,4-difluorophenyl)-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, m.p. 226°-228° C., pale yellow crystals (recrystallized fromethanol)

27)7-(1-Piperazinyl)-1-(2,4-difluorophenyl)-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid hydrochloride, m.p. 229°-232° C., white crystals (recrystallizedfrom ethanol - water)

28)7-(3-Amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid hydrochloride, m.p. 291°-294° C., white crystals (recrystallizedfrom ethanol - water)

Example 6

A mixture comprising7-(3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (trans form) (120 mg), ethanol (4 ml) and 10% hydrochloric acid (4ml) is refluxed for 30 minutes After concentrating, the obtained residueis recrystallized from methanol - ethyl acetate to give7-(3-amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid hydrochloride (trans form) (60 mg), as white powder, m.p. 272°-275°C.

Starting from suitable materials, the procedure of Example 6 is repeatedto give the following compounds.

1)7-(3-Amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid hydrochloride (cis form), m.p. 280°-284° C. (dec.), pale yellowpowder (recrystallized from ethanol)

2)7-(3-Ethylaminomethyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid hydrochloride, m.p. 236°-239° C., pale yellow powder(recrystallized from ethanol)

3)7-(3-Methylamino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, m.p. 194°-197° C., white powder (recrystallized fromdimethylformamide)

4)7-(3-Amino-1-pyrrolidinyl)-1-(4-fluorophenyl)-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid hydrochloride, m.p. 292°-295° C. (dec.), pale yellow crystals(recrystallized from methanol - water)

5)7-(3-Amino-1-pyrrolidinyl)-1-ethyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid hydrochloride, m.p. 275°-281° C. (dec.), yellowish crystals(recrystallized from ethanol)

Example 7

To a solution of7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (40 mg) in 5% sodium hydroxide (2 ml) is added acetic anhydride(0.1 ml) at room temperature. After the mixture is made acidic withdilute hydrochloric acid, the resultant product is extracted withdichloromethane and the extract is dried over magnesium sulfate. Afterconcentrating, the obtained residue is recrystallized from ethanol togive 7-(4-acetyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (29 mg), as white powder, m.p. 261°-263° C.

Example 8

To a solution of1-cyclopropyl-6-fluoro-7-bromo-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (0.58 g) in N-methyl-2-pyrrolidone (5 ml) is added 4-oxopiperidine(0.64 g) and the mixture is heated at 90° C. for 20 minutes The solventis distilled off under reduced pressure To the resulting residue isadded ethanol and the precipitated crystals are filtered to give1-cyclopropyl-6-fluoro-7-(4-oxo-1-piperidinyl)-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (230 mg).

Elementary Analysis for C₁₉ H₁₉ N₂ O₄ F Calcd. (%): C, 63.68; H, 5.34;N, 7.82 Found (%): C, 63.58; H, 5.39; N, 7.72

Experiment (Antimicrobial activity in vitro)

The antimicrobial activity of the test compounds as mentioned below wastested by measuring minimum inhibitory concentration (MIC) by the serialdilution method on agar plate [cf. Chemotherapy, 22, 1126-1128 (1974)].The microorganisms were used in a concentration of 1×10⁶ cells/ml (0.D.660 mμ, 0.07-0.16, 100 folds dilution). The results are shown in Table1.

[Test compounds]:

1.7-(4-Methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid

2.7-(1-Piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid

3.7-(3-Amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid

4.7-(3-Methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid

5.7-(3-Aminomethyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid hydrochloride

6.7-(3-Amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid hydrochloride (trans form)

7.7-Morpholino-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid

8.7-(3-Ethylaminomethyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid hydrochloride

9.7-(1,4-Diazabicyclo[4,3,0]nonan-4-yl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid

10.7-(4-Hydroxy-1-piperidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid

11.7-(4-Fluoro-1-piperidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid

12.7-(3-Amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (cis form)

13.7-(4-Acetyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid

14.7-(3-Methylamino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid

15.7-(1-Piperazinyl)-1-(4-fluorophenyl)-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid

16.7-(3-Amino-1-pyrrolidinyl)-1-(4-fluorophenyl)-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid hydrochloride

17.7-(4-Methyl-1-piperazinyl)-1-(4-fluorophenyl)-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid

18.7-(4-Methyl-1-piperazinyl)-1-(2,4-difluorophenyl)-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid

19.7-(1-Piperazinyl)-1-(2,4-difluorophenyl)-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid hydrochloride

20.7-(3-Amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid hydrochloride

[Test microorganisms]:

A: Staphylococcus aureus FDA 209P

B: Staphylococcus aeruginosa E-2

                  TABLE 1                                                         ______________________________________                                                       Microorganisms                                                 Test compounds   A       B                                                    ______________________________________                                         1               0.195   0.78                                                  2               0.098   0.39                                                  3               0.098   0.39                                                  4               0.098   0.39                                                  5               0.098   1.56                                                  6               0.195   0.78                                                  7               0.098   --                                                    8               0.195   --                                                    9               0.049   0.78                                                 10               0.049   --                                                   11               0.098   --                                                   12               0.195   0.78                                                 13               0.098   --                                                   14               0.098   0.78                                                 15               0.049   0.39                                                 16               0.098   0.39                                                 17               0.195   1.56                                                 18               0.098   1.56                                                 19               0.098   0.39                                                 20               0.024   0.78                                                 ______________________________________                                    

Preparation 1

An injection preparation is prepared from the following components.

    ______________________________________                                        Components            Amount                                                  ______________________________________                                        7-(1-Piperazinyl)-1-cyclopropyl-6-                                                                  200 mg                                                  fluoro-5-methyl-1,4-dihydro-4-oxo-                                            quinoline-3-carboxylic acid                                                   Glucose               250 mg                                                  Distilled water for injection                                                                       q.s.                                                    Totally                5 m                                                    ______________________________________                                    

7-(1-Piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid and glucose are dissolved in distilled water for injection, and thesolution is added to a 5 ml ampoule, which is purged with nitrogen gasand then subjected to sterilization at 121° C. for 15 minutes to give aninjection preparation.

Preparation 2

Film coated tablets are prepared from the following components.

    ______________________________________                                        Components                 Amount                                             ______________________________________                                        7-(3-Methyl-1-piperazinyl)-1-cyclopropyl-6-                                                              100 g                                              fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-                                   3-carboxylic acid                                                             Avicel (tradename of microcrystalline cellulose,                                                          40 g                                              manufactured by Asahi Chemical Industry                                       Co., Ltd., Japan)                                                             Corn starch                 30 g                                              Magnesium stearate          2 g                                               TC-5 (tradename of hydroxypropyl methylcellulose,                                                         10 g                                              manufactured by The Shin-Etsu Chemical Co.,                                   Ltd., Japan)                                                                  Polyethylene glycol 6000    3 g                                               Castor oil                  40 g                                              Ethanol                     40 g                                              ______________________________________                                    

7-(3-Methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, Avicel, corn starch and magnesium stearate are mixed and kneadedand the mixture is tabletted using a conventional pounder (R 10 mm) forsugar coating (manufactured by Kikusui Seisakusho Co., Ltd., Japan). Thetablets thus obtained are coated with a film coating agent consisting ofTC-5, polyethylene glycol 6000, castor oil and ethanol to give filmcoated tablets.

Preparation 3

An ointment is prepared from the following components.

    ______________________________________                                        Components                  Amount                                            ______________________________________                                        7-(4-Methyl-1-piperazinyl)-1-cyclopropyl-6-                                                                2 g                                              fluoro-5-methyl-1,4-dihydro-4-oxo-                                            quioline-3-carboxylic acid                                                    Purified lanolin             5 g                                              Bleached beeswax             5 g                                              White Vaseline               88 g                                             Totally                     100 g                                             ______________________________________                                    

Bleached beeswax is made liquid by heating, and thereto are added7-(4-methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, purified lanolin and while vaseline, and the mixture is heateduntil it becomes liquid. The mixture is stirred until it is solidifiedto give an ointment.

What is claimed is:
 1. A compound of the formula: ##STR36## wherein R¹is a cyclopropyl which is optionally substituted by 1 to 3 substituentsselected from the group consisting of a (lower) alkyl and a halogenatom, provided that when R¹ is unsubstituted cyclopropyl R³ is methyl; aphenyl which is optionally substituted by 1 to 3 substituents selectedfrom the group consisting of a (lower) alkoxy, a halogen atom andhydroxy; a (lower) alkyl which is optionally substituted by a halogenatom, a (lower) alkanoyloxy or hydroxy; a (lower) alkenyl; or thienyl,R³is a (lower) alkyl group, R¹⁴ is hydrogen atom, a lower alkyl group, ora group of the formula: ##STR37## wherein R¹⁵ and R¹⁶ are each a (lower)alkyl group, X is a halogen atom, and X⁴ is a halogen atom, or apharmaceutically acceptable salt thereof.
 2. The compound according toclaim 1, wherein R¹ is a phenyl which is optionally substituted by 1 to3 substituents selected from the group consisting of a C₁ -C₆ alkoxygroup, a halogen atom and hydroxy group, or a C₁ -C₆ alkyl group whichis optionally substituted by a halogen atom, a C₂ -C₆ alkanoyloxy groupor hydroxy group, R¹⁴ is hydrogen atom, and X is fluorine atom or apharmaceutically acceptable salt thereof.
 3. The compound according toclaim 1, wherein R¹ is a C₂ -C₆ alkenyl group or thienyl group, R¹⁴ ishydrogen atom, and X is fluorine atom, or a pharmaceutically acceptablesalt thereof.
 4. The compound according to claim 1, wherein R¹ is acyclopropyl which is optionally unsubstituted or substituted by 1 to 3of substituents selected from the group consisting of a C₁ -C₆ alkyl anda halogen atom; a phenyl which is optionally unsubstituted orsubstituted by 1 to 3 of substituents selected from the group consistingof a C₁ -C₆ alkoxy, a halogen atom and hydroxy; a C₁ -C₆ alkyl which isoptionally unsubstituted or substituted by a halogen atom, a C₂ -C₆alkanoyloxy or hydroxy; a C₂ -C₆ alkenyl; or thienyl,R³ is a C₁ -C₆alkyl, R¹⁴ is hydrogen atom, a C₁ -C₆ alkyl, or a group of the formula:##STR38## wherein R¹⁵ and R¹⁶ are each a C₁ -C₆ alkyl, or apharmaceutically acceptable salt thereof.
 5. The compound according toclaim 4, wherein R³ is methyl or ethyl, or a pharmaceutically acceptablesalt thereof.
 6. The compound according to claim 5, wherein X ischlorine or fluorine atoms or a pharmaceutically acceptable saltthereof.
 7. The compound according to claim 6, wherein R¹ isunsubstituted cyclopropyl, or a pharmaceutically acceptable saltthereof.
 8. The compound according to claim 6, wherein R¹ is a phenylwhich is optionally unsubstituted or substituted by 1 to 3 ofsubstituents selected from the group consisting of a C₁ -C₆ alkoxy, ahalogen atom and hydroxy; or a C₁ -C₆ alkyl which is optionallyunsubstituted or substituted by a halogen atom, a C₂ -C₆ alkanoyloxy orhydroxy, or a pharmaceutically acceptable salt thereof.
 9. The compoundaccording to claim 6, wherein R¹ is a C₂ -C₆ alkenyl or thienyl, or apharmaceutically acceptable salt thereof.
 10. The compound according toany one of claim 7, 8 or 9, wherein R¹⁴ is hydrogen atom, or a saltpharmaceutically acceptable thereof.
 11. The compound according to anyone of claim 7, 8 or 9, wherein R¹⁴ is a C₁ -C₆ alkyl, or apharmaceutically acceptable salt thereof.
 12. The compound according toany one of claim 7, 8 or 9, wherein R¹⁴ is a group of the formula:##STR39## wherein R¹⁵ and R¹⁶ are each a C₁ -C₆ alkyl, or apharmaceutically acceptable salt thereof.
 13. Ethyl1-cyclopropyl-6,7-difluoro-5-methyl-1,4-dihydro-4-oxoquinonline-3-carboxylate.14.1-Cyclopropyl-6,7-difluoro-5-methyl-1,4-dihydro-4-oxoquinonline-3-carboxylicacid.
 15. Ethyl1-(4-fluorophenyl)-6,7-difluoro-5-methyl-1,4-dihydro-4-oxoquinonline-3-carboxylate.16.1-(4-Fluorophenyl)-6,7-difluoro-5-methyl-1,4-dihydro-4-oxoquinonline-3-carboxylicacid.
 17. Ethyl1-ethyl-6,7-difluoro-5-methyl-1,4-dihydro-4-oxoquinonline-3-carboxylate.18.1-Ethyl-6,7-difluoro-5-methyl-1,4-dihydro-4-oxoquinonline-3-carboxylicacid.
 19. Ethyl1-cyclopropyl-6-fluoro-7-bromo-5-methyl-1,4-dihydro-4-oxoquinonline-3-carboxylate.20.1-Cyclopropyl-6-fluoro-7-bromo-5-methyl-1,4-dihydro-4-oxoquinonline-3-carboxylicacid. 21.1-Cyclopropyl-6-fluoro-7-chloro-5-methyl-1,4-dihydro-4-oxoquinonline-3-carboxylicacid.
 22. Ethyl1-(2,4-difluorophenyl)-6,7-difluoro-5-methyl-1,4-dihydro-4-oxoquinonline-3-carboxylate.23.1-(2,4-Difluorophenyl)-6,7-difluoro-5-methyl-1,4-dihydro-4-oxoquinonline-3-carboxylicacid.
 24. The compound according to claim 1, wherein R¹ is unsubstitutedcyclopropyl, R¹⁴ is hydrogen atom, X is fluorine atom and R³ is amethyl, or a pharmaceutically acceptable salt thereof.